SK19252001A3 - Indazole compounds and pharmaceutical compositions for inhibiting protein kinases, and methods for their use - Google Patents

Abstract

Indazole compounds that modulate and/or inhibit the activity of certain protein kinases are described. These compounds and pharmaceutical compositions containing them are capable of mediating tyrosine kinase signal transduction and thereby modulate and/or inhibit unwanted cell proliferation. The invention is also directed to the therapeutic or prophylactic use of pharmaceutical compositions containing such compounds, and to methods of treating cancer and other disease states associated with unwanted angiogenesis and/or cellular proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis, and psoriasis, by administering effective amounts of such compounds.

Description

Technical field

The present invention relates to indazole compounds that mediate and / or inhibit the activity of certain protein kinases, and pharmaceutical compositions containing these compounds. The invention also relates to the therapeutic or prophylactic use of these compounds and compositions, and further to the treatment of cancers as well as other disease states associated with undesired angiogenesis and / or cell proliferation by administering an effective amount of these compounds.

BACKGROUND OF THE INVENTION

Protein kinases are a group of enzymes that catalyze the phosphorylation of the hydroxyl group of specific tyrosine, serine or threonine residues in proteins. This phosphorylation typically significantly disrupts protein function and protein kinases are therefore key enzymes for the regulation of a variety of cellular processes. including metabolism, cell proliferation, cell differentiation and cell survival. Of the many different cellular functions known to be necessary for protein kinase activity, some processes represent attractive targets for therapeutic intervention in certain disease states. Two examples are angiogenesis and cell cycle control, where protein kinases play a major role, these processes being essential for the growth of solid tumors as well as for other diseases.

the mechanism by which new ones are created

Angiogenesis is a capillary from existing vessels. If necessary, the vascular system has the potential to create new capillary networks to maintain proper tissue and organ function. However, in adults, angiogenesis is rather limited, occurring only in the process of wound healing and neovascularization of the endometrium during menstruation. (See Merenmies et al.,

Cell Growth &

Differentiation, 8, 3-10, 1997).

On the other hand, undesirable angiogenesis is a hallmark of several diseases such as retinopathy, psoriasis, rheumatoid arthritis, age-related macular degeneration (AMD) and cancers (solid tumors). (Folkman, Nature Med., 1, 27-31, 1995). Protein kinases that have been shown to be involved in the angiogenic process include three members of the growth factor receptor tyrosine kinase family: VEGF-R2 (vascular endothelial growth factor receptor 2, also known as KDR (kinase domain receptor) and FLK-1) , FGF-R (fibroblast growth factor receptor) and TEK (also known as Tie-2).

VEGF-R2, which is expressed only on endothelial cells, binds potent angiogenic growth factor VEGF and mediates downstream signal transduction by activating its intracellular kinase activity. Thus, direct inhibition of VEGF-R2 kinase activity is expected to result in a reduction in angiogenesis even in the presence of exogenous VEGF (see Strawn et al., Cancer Research, 56, 3540-3545, 1996), as shown in VEGF- mutants. R2 which are not able to mediate signal transduction. (Millauer et al., Cancer Research 56,

1615-1620, 1996). In addition, it appears that VEGF-R2 has no other function in adults other than mediating the angiogenic activity of VEGF.

Thus, a selective inhibitor of kinase activity is expected

VEGF-R2 would exhibit low toxicity.

Similarly, FGF-R binds angiogenic growth factors aFGF and bFGF and mediates subsequent intracellular signal transduction. It has recently been suggested that growth factors such as bFGF may play a key role in inducing angiogenesis in solid tumors that have reached a certain size. (Yoshiji et al., Cancer Research 57: 3924-3928, 1997). However, unlike VEGF-R2, FGF-R is expressed in a number of different cell types throughout the body and may or may not play an important role in other normal physiological processes in adults. However, systemic administration of a small molecule inhibitor that inhibited FGF-R kinase activity has been reported to block bFGF-induced angiogenesis in mice without apparent toxicity. (Mohamrnad et al., EMBO Journal, 17, 5996-5904, 1998).

TEK (also known as Tie-2) is another receptor tyrosine kinase expressed only on endothelial cells that has been shown to play a role in angiogenesis. Angiopoietin-1 binding results in autophosphorylation of the TEK kinase domain and results in a signal transduction that is likely to mediate the interaction of endothelial cells with peri-endothelial feeder cells, thereby facilitating maturation of newly formed blood vessels. On the other hand, angiopoietin-2 factor is likely to antagonize the effect of angiopoietin-1 on TEK and disrupt angiogenesis. (Maisonpierre et al., Science, 277, 55-60, 1997).

As a consequence of the above research, it has been suggested to treat angiogenesis using compounds that inhibit VEGF-R2, FGF-R and / or TEK kinase activity. For example, WIPO International Publication no. WO 97/34876 discloses certain cinnoline derivatives that are VEGF-R2 inhibitors that can be used to treat disease states associated with abnormal angiogenesis and / or increased vascular permeability, such as carcinomas, diabetes, psoriasis, rheumatoid arthritis, Kaposi's sarcoma, haemangioma, acute and chronic nephropathy, atheroma, arterial restenosis, autoimmune diseases, acute inflammation and eye diseases with retinal vascular proliferation.

Phosphorylase kinase activates glycogen phosphorylase, thus increasing glycogen breakdown and glucose release by the liver. Regulation of hepatic glucose production is impaired in type 2 diabetes and is the primary cause of fasting hyperglycaemia, resulting in many secondary complications affecting these patients. Thus, reducing the release of glucose from the liver would reduce the elevated plasma glucose level. Thus, phosphorylase kinase inhibitors would decrease phosphorylase activity and glycogenolysis and thus reduce hyperglycemia in patients.

Another physiological response to VEGF is vascular hyperpermeability, which is believed to play a role in the early stages of angiogenesis. In ischemic tissues, such as those found in the brain of victims of stroke, hypoxia triggers VEGF expression, leading to increased vascular permeability and ultimate edema of adjacent tissues. In a stroke model in rats, van Bruggen et al. (J. Clinical Invest., 104, 1613-20, 1999) that administration of a monoclonal antibody to VEGF reduces infarct volume. Thus, VEGFR inhibitors are expected to be useful in the treatment of stroke.

In addition to their role in angiogenesis, protein kinases also play a very important role in cell cycle control. Uncontrolled cell proliferation is a major feature of cancer. Cell proliferation in response to various stimuli is manifested by deregulation of the cell division cycle, the process by which cells proliferate and divide. Tumor cells typically have damaged genes that directly or indirectly regulate the progression of the cell division cycle.

Cyclin-dependent kinases (CDKs) are serintreonine protein kinases that play a critical role in regulating transitions between different phases of the cell cycle. (See, e.g., articles reviewed in Science, 274, 1643-1677, 1996). CDK complexes are formed by linking a regulatory cyclin subunit (e.g.

cyclin A, BI, B2, name whispers,

D1, D2, D3, and E) and catalytic kinase subunit (e.g., cdc2 (CDK1), CDK2, CDK4, CDK5, and CDK6). Than

CDKs exhibit absolute cyclin subunit dependence in phosphorylation of their target substrates, and different kinase / cyclin pairs act to regulate the progression of specific phases of the cell cycle.

It is a complex of CDK4 with cyclins D that plays a critical role in initiating a cell division cycle from a resting or resting stage to the stage where cells begin to undergo cell division. This progression is subject to a variety of growth regulatory mechanisms, both negative and positive. Deviations in this control system, particularly those affecting CDK4 function, are involved in the further development of cells to a highly proliferative state characteristic of malignancies, namely familial melanomas, esophageal carcinomas and pancreatic carcinomas. (See, e.g., Kamb, Trends in Genetics, 11, 136-140, 1995; Kamb et al., Science, 264, 436-440, 1994).

Numerous publications describe a variety of chemical compounds useful against a variety of therapeutic targets. For example, WIPO International Application Nos. WO 99/23077 and WO 99/23076 disclose indazole-containing compounds having type IV phosphodiesterase inhibitory activity produced by bioisosteric replacement of catechol with indazole. U.S. Pat. No. 5,760,028 discloses a heterocycle comprising.

3- [1- [3- (imidazolin-2-ylamino) propyl] indazol-5-ylcarbonylamino] -2- (benzyloxycarbonylamino) propionic acid, which are useful as antagonists of αβ ₃ integrin and related adhesive protein receptors of the cell surface. WIPO International Application no. WO 98/09961 discloses certain indazole derivatives and their use as inhibitors of phosphodiesterase (PDE) type IV or the production of tumor necrosis factor (TNF) in mammals. Recent contributions to the virtual library of known compounds include compounds described as antiproliferative therapeutic agents that inhibit CDRs. For example, U.S. Pat. No. 5,621,082 to Xiong et al. Discloses a nucleic acid encoding a CDK6 inhibitor and European patent application no. No. 0 666 270 A2 discloses peptides and peptidomimetics which act as inhibitors of CDK1 and CDK2. International patent application no. WO 97/16447 discloses certain chromate analogs which are inhibitors of cyclin-dependent kinases, particularly CDK / cyclin complexes such as CDK4 / cyclin D1, which can be used to inhibit excessive or abnormal cell proliferation and thus for the treatment of cancer. WIPO International Application no. WO 99/21845 discloses 4-aminothiazole derivatives, inhibitors.

which are useful as CDKs

However, there remains a need for small molecule compounds (small molecules) that can be readily synthesized and effectively inhibit one or more CDKs or CDK / cyclin complexes. Since CDK4 can serve as a general cell division activator in most cells, and the CDK4 and D-type cyclin complexes control the early Gi phase of the cell cycle, there is a need for potent CDK4 inhibitors and their D-type cyclin complexes for the treatment of one or more tumor types. Also, a significant role of kinases, cyclin E / CDK2 and cyclin B / CDK1 phase transitions in the Gi / S and G ₂ / M, respectively, provide additional targets for therapeutic intervention in suppressing deregulated cell-cycle progression in cancer.

Another protein kinase, CHK1, plays an important role as a checkpoint in cell cycle progression. Control points are control systems that coordinate cell cycle progression by influencing the formation, activation and subsequent inactivation of cyclin-dependent kinases. Control points prevent cell cycle progression at inappropriate times, maintain the metabolic balance of cells when cells are held at a certain stage (arest), and in some cases may induce apoptosis (programmed cell death) when the control point conditions are not met. (See, e.g., O'Connor, Cancer Surveys, 29, 151-182, 1997), Nurse, Cell, 91, 865-867, 1997), Hartwell et al.,

Science, 266, 1821-1828 (1994); Hartwell et al., Science, 246,

629-634, 1989).

One series of checkpoints monitors the integrity of the genome and for sensing DNA damage, these "DNA damage checkpoints block the progression of the cell cycle phases Gi and G ₂ and slowing the progression of S phase. (O'Connor, Cancer Surveys, 29, 151-182,

1997, Hartwell et al., Science, 266, 1821-1828 (1994). This effect allows DNA repair processes to be stopped before genome replication and until the subsequent separation of genetic material into new daughter cells takes place. Importantly, the most commonly mutated gene in human cancers, the p53 tumor suppressor gene, creates a protein for a DNA damage checkpoint that blocks cell cycle progression in the Gi phase and / or induces apoptosis (programmed cell death) upon DNA damage. (Hartwell et al., Science, 266, 1821-1828.

1994). The tumor suppressor gene p53 has also been shown to enhance the effect of a checkpoint for DNA damage in the G ₂ phase of the cell cycle. (See, e.g., Bunz et al., Science, 28, 14971501, 1998), Winters et al., Oncogene, 17, 673-684, 1998),

Thompson, Oncogene 15: 3025-3035 (1997).

Due to the intrinsic nature of the human cancers pathway, intervention that the tumor suppressor gene p53 in therapeutic cancers is actively sought for vulnerability to exploit the discovered vulnerability lies in p53 surgery. cells particularly defective in p53. One checkpoint G ₂ in cancer cells defective in cancer because they lack the checkpoint Gi are vulnerable to removal of the last remaining barrier protecting them from likvidujúcimi tumor ( "cancer-killing) effects of DNA-damaging agents: Control Point G _2nd Control point G ₂ is regulated by a control system that is maintained from yeast to human. Important in this conserved system is the kinase, CHK1, which transduces signals from a DNA damaging complex to inhibit the activation of the cyclin B / Cdc2 kinase that promotes entry into the mitotic phase (see, e.g., Peng et al., Science, 277, 1501-1505 , 1997, Sanchez et al., Science, 277: 1497-1501 (1997). It has been shown that inactivation of CHK1 deleted as _G2 Arest induced DNA damage caused by either anticancer agents or endogenous DNA damage, as well as results in preferential killing of cells defective in the subsequent control points (see e.g., Nurse, Cell, 91, 865-867, 1997 Weinert, Science, 277, 1450-1451, 1997, Walworth et al., Nature, 363, 368-371, 1993, and Al-Khodairy et al., Molec. Biol. Cell, 5, 147-160, 1994).

The selective manipulation of a checkpoint in cancer cells could provide wide use in chemotherapy and radiotherapy regimens in the treatment of cancer and may additionally provide a general feature of "genomic instability of human cancers to be investigated as a selective basis for cancer cell destruction. A number of factors have CHK1 as an essential target for the DNA damage checkpoint. Clarification of inhibitors of this and functionally related kinases such as Cdsl / ₂ CHK kinase of which was recently discovered to cooperate with CHK1 in regulating S phase progression (see. Zeng et al., Nature, 395, 507-510, 1998 , Matsuoka, Science, 282, 1893-1897, 1998) could provide a valuable new therapeutic basis for the treatment of cancer.

Binding of the integrin receptor to the ECM initiates intracellular signals mediated by FAK (focal adhesion kinase), which are involved in cell motility, cell proliferation and survival. In human cancers, FAK overexpression is involved in tumor genesis and metastatic potential due to its role in integrin-mediated signaling pathways.

having extracellular, transmembrane

Tyrosine kinases can generally be of the receptor type (i.e., and intracellular domains) or of the non-receptor type (i.e., are fully intracellular). It is believed that at least one non-receptor protein tyrosine kinase, namely

LCK, mediates in T lymphocytes the signal transduction of the cell surface protein (Cd4) interaction by a cross-linked anti-Cd4 antibody (a more detailed discussion of non-receptor tyrosine kinases is reported

2025-2031, 1993, which is the work of Bolen, Oncogene, 8, incorporated herein by reference).

In addition to the protein kinases identified above, many other protein kinases have been found to be therapeutic targets and numerous publications describe inhibitors of kinase activity as reviewed in the following works (McMahon et al, Oncologist, 5, 3-10, 2000, Holash et al., Oncogene, 18, 5356-62 (1999)

Thomas et al., J. Biol. Chem., 274, 36684-92 (1999), Cohen,

Curr. Op. Chem. Biol., 3, 459-65, 1999, Klohs. et al., Curr.

Op. Chem. Biol., 10, 544-49, 1999; McMahon et al., Current

Opinion in Drug Discovery & Development, 1998, 1, 131-146.

Strawn et al., Exp. Opin. Invest. Drugs, 7: 553-573 (1998).

International patent application WO 00/18761 discloses certain substituted 3-cyanoquinolines as protein kinase inhibitors.

However, there remains a need for potent protein kinase inhibitors. In addition, as is clear to those skilled in the art, it is desirable that kinase inhibitors have both a high affinity for the target kinase or kinases, and also be highly selective in comparison to other protein kinases.

SUMMARY OF THE INVENTION

It is an object of the invention to provide potent inhibitors of protein kinases. It is a further object of the invention to provide potent kinase inhibitors having a strong and selective affinity for one or more particular kinases.

These and other objects of the invention, which will be clear from the following description, have been achieved by the discovery of the indazole compounds, their pharmaceutically acceptable prodrugs, pharmaceutically active metabolites and pharmaceutically acceptable salts (these compounds, prodrugs, metabolites and salts are collectively referred to as "agents" or "agents"). described below that modulate and / or inhibit the activity of protein kinases. Pharmaceutical compositions containing these agents are useful in the treatment of diseases mediated by kinase activity, such as carcinomas, as well as other disease states associated with undesired angiogenesis and / or cell proliferation, such as diabetic retinopathy, neovascular glaucoma, rheumatoid arthritis and psoriasis. Further, the agents have advantageous properties regarding the modulation and / or inhibition of the kinase activity associated with VEGF-R, FGFR, CDK, CHK1, LCK, TEK, FAK and / or phosphorylase kinase complexes.

In a general aspect, the invention relates to compounds of formula I:

where:

R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ³ or CH = NR ³ wherein R ³ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group and

R ² is a substituted or unsubstituted aryl, heteroaryl or YX group, wherein Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , alkylidene, NH or

N-C 1 -C 8 -alkyl and X is substituted or unsubstituted Ar, heteroaryl,

NH-alkyl, NH-cycloalkyl heterocycloalkyl, NH-aryl heteroaryl, NH-alkoxy

group, NH- group, NH- or NH-

a dialkylamido group wherein Ar is an aryl group.

The invention also relates to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites and pharmaceutically acceptable salts of the compound of formula I.

Also preferred methods of making the compounds of formula I are described.

In another general aspect, the invention

I (a)

H refers to compounds of the formula wherein:

R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ³ or CH = NR ³ wherein R ³ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group and

R ² is a substituted or unsubstituted aryl or Y-Ar, where Y is 0, S, C = _CH2, C = O, S = 0, a group of S0 _2, CH _2, a group CH-CH ₃ group, NH or N-C 1 -C 8 alkyl and Ar is a substituted or unsubstituted aryl group.

The invention also relates to pharmaceutically acceptable prodrugs, pharmaceutically active metabolites and pharmaceutically acceptable salts of a compound of formula I (a). Preferred processes for preparing the compounds of formula I (a) are also described.

In one preferred general embodiment, the invention relates to compounds having the formula II:

where:

R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ^3, or

CH = NR ³ , wherein R ³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group,

R ⁴ and R ⁷ are each independently hydrogen, OH, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkenyl, aryloxy, thioaryl, ΟΗ _2- (CH ₂ -O-C 1 -C 8) alkyl, CH ₂ -O-aryl, CH ₂ -S (C 1 -C 8) alkyl or CH ₂ -Saryl,

R ⁵ and R ⁶ are each independently hydrogen, OH, halogen, Z-alkyl, Z-aryl or Z-CH ₂ CH = CH ₂ , wherein Z is O, S, NH or CH ₂ and the alkyl group and the aryl group of z-alkyl and Zarylovej group is optionally substituted, and pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof.

In a preferred embodiment of Formula II: R ¹ is a substituted or unsubstituted bicyclic heteroaryl group or a group of formula CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted aryl or heteroaryl group, R ⁴ and R ⁷ are each independently hydrogen or alkyl a group containing 1 to 8 carbon atoms and R ⁵ and R ⁶ are each independently halogen, Z-alkyl or Z-CH ₂ CH = CH ₂ , wherein Z is O or S.

In another preferred general embodiment, the compounds of the invention are of formula III:

where:

R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ³ or CH = NR ³ , wherein R ³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group,

Y is O, S, C = CH 2, C = O, S = O, SO ₂ , CH ₂ , CHCH ₃ , NH or C 1 -C 8 -alkyl,

R ⁸ is substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy or aryloxy,

R ¹⁰ is independently selected from the group consisting of hydrogen, halogen and lower alkyl

And pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.

More preferably in formula III: R ¹ is a substituted or unsubstituted bicyclic heteroaryl group or a group of formula CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted aryl or heteroaryl group, Y is O, S, C = CH ₂ , C = O, NH or N-C 1 -C 8 -alkyl,

R ⁸ is substituted or unsubstituted aryl, heteroaryl, alkyl and alkenyl, and R 10 is hydrogen or halogen.

In another preferred general embodiment, the compounds of the invention are of formula III (a):

m (a) H wherein;

R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ³ or CH = NR ³ , wherein R ³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group,

Y is O, S, C = CH 2, C = O, S = O, SO ₂ , CH ₂ , CHCH ₃ , NH or N-alkyl containing up to 8 carbon atoms,

R ⁸ is substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy or aryloxy,

And pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.

More preferably in Formula III (a): R ¹ is a substituted or unsubstituted bicyclic heteroaryl group or a group of formula CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted aryl or heteroaryl group, Y is O, S, C = CH ₂ , C = O, NH or N-C 1 -C 8 alkyl, and R ⁸ is substituted or unsubstituted aryl or heteroaryl.

In another preferred general embodiment, the compounds of the invention are of formula IV:

R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ³ or CH = NR ³ , wherein R ³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group,

Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , CH _{2 /} CHCH ₃ , NH or N-C 1 -C 8 -alkyl,

R ₉ is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkoxy, NH 1 -C 8 alkyl, NH-aryl, NH-heteroaryl, N = CH-alkyl, NH (C = O) R ^{1, L,} or NH ₂ , wherein R ¹¹ is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl and

R ¹⁰ is independently selected from the group consisting of hydrogen, halogen and lower alkyl

And pharmaceutically acceptable prodrugs, pharmaceutically acceptable metabolites, and pharmaceutically acceptable salts thereof.

More preferably in formula IV: R ¹ is a group of formula CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted aryl or heteroaryl group, Y is S or NH and

R ⁹ is a substituted or unsubstituted alkyl, alkoxy or NH-heteroaryl group.

Most preferably, the compounds of the invention are selected from the group consisting of:

Μ

The invention also relates to a method of modulating and / or inhibiting the kinase activity of VEGF-R, FGF-R, the CDK complex, CHK1, LCK,

TEK, FAK and / or phosphorylase kinase by administration of a compound of formula or IV or a pharmaceutically acceptable pharmaceutically active metabolite of an acceptable salt thereof. Preferred compounds

I, II,

III of a prodrug, pharmaceutical or according to the present activity, i.

of the invention, have significant more specific kinases, minimal activity against one having selective kinase activity against one or having small or different kinases. In a compound of the present invention, while one or more preferred embodiments of the invention are the present invention, compounds of formula I that have substantially greater activity against VEGF receptor tyrosine kinase than against FGF-R1 receptor tyrosine kinase. The invention also relates to a method of modulating VEGF receptor tyrosine kinase activity without significantly modulating FGF receptor tyrosine kinase activity.

The compounds of the invention may be used advantageously in combination with other known therapeutic agents. For example, compounds of Formula I, II, III or IV having anti-angiogenic activity may be co-administered with cytotoxic chemotherapeutic agents such as taxol, taxotere, vinblastine, cis-platin, doxorubicin, adriamycin and the like to provide enhanced anti-tumor activity. . Additive or synergistic enhancement of the therapeutic effect may also be obtained by co-administering compounds of formula I, II, III or IV having antiangiogenic activity with other anti-angiogenic agents such as combretastatin A-4, endostatin, prinomastat, celecoxib, rofocoxib, EMD121974 IM862, an anti-VEGF monoclonal antibody and an anti-KDR monoclonal antibody.

The invention also relates to pharmaceutical compositions comprising an effective amount of an agent selected from the group consisting of compounds of Formula I and its salts, pharmaceutically active acceptable prodrugs and acceptable pharmaceutical pharmaceutical metabolites, and a pharmaceutically acceptable carrier or vehicle thereof. The invention further provides for the treatment of cancer, as well as other disease states associated with undesired angiogenesis and / or cell proliferation, comprising administering to a patient in need thereof an effective amount of such an agent.

Detailed description of the invention and preferred embodiments

Compounds of the Invention of Formulas I, II Useful More specifically for mediating activity, compounds useful as agents and as

III and IV are protein kinases. anti-angiogenic agents to modulate and / or inhibit activity and thus are useful in the treatment of cancer or associated with cellular proliferation of protein kinases, other protein kinase mediated diseases.

As used herein, the term "alkyl" refers to straight and branched chain alkyl groups having one to twelve carbon atoms. Examples of alkyl groups are: methyl, (Me), ethyl (Et), n-propyl, isopropyl, butyl isobutyl, sec-butyl, tert (t-Bu), pentyl, isopentyl, hexyl "isohexyl" denotes lower alkyl. 1 to 8 carbon atoms (alkyl group of carbon atoms). Suitable substituted tert-pentyl and the like. The term having a group, a butyl group, an alkyl group containing 1 to 8 alkyl groups are: fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl, 324 fluoropropyl, hydroxymethyl, 2-hydroxyethyl, 3-hydroxypropyl and the like.

The term "alkylidene" refers to a divalent radical having one to twelve carbon atoms. Examples of alkylidene groups include CH ₂ , CHCH ₃ , (CH ₃ ) _2, and the like.

The term "alkenyl" refers to straight and branched chain alkenyl groups having two to twelve carbon atoms. Examples of alkenyl groups include prop-2-enyl, but-2-enyl, but-3-enyl, 2-methylprop-2-enyl, hex-2-enyl and the like.

The term "alkynyl group" refers to straight and branched chain alkynyl groups having two to twelve carbon atoms.

The term "cycloalkyl" refers to saturated or partially unsaturated carbocycles having three to twelve carbon atoms, including bicyclic and tricyclic cycloalkyl structures. Suitable cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.

The term "heterocycloalkyl" means a saturated or partially unsaturated monocyclic radical containing carbon atoms, preferably 4 or 5 ring carbon atoms, and at least one heteroatom selected from nitrogen, oxygen and sulfur atoms.

The terms "aryl and" heteroaryl refer to monocyclic and polycyclic unsaturated or aromatic ring structures, the term "aryl" refers to carbocycles and "heteroaryl" refers to heterocycles. Examples of aromatic ring structures are:

phenyl, naphthyl,

1,2,3,4tetrahydronaphthyl, furyl, thienyl, pyrrolyl, pyridinyl, pyrazolyl, imidazolyl, pyrazinyl, pyridazinyl, 1,2,3-triazinyl,

1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1H-tetrazol-5-yl, indolyl, quinolinyl, benzofuranyl, benzothiophenyl (thianaphthenyl) and the like. These groups may be optionally substituted by fused ring structures or bridges, for example OCH ₂ -O.

The term "alkoxy" means a radical-O-alkyl group. Examples include methoxy, ethoxy, propoxy and the like.

The term "aryloxy" represents an -O-aryl group, wherein the aryl group is as defined above.

The term "cycloalkoxy" represents -O-cycloalkyl, wherein the cycloalkyl group is as defined above.

The term "halogen atom" represents a chlorine, fluorine, bromine or iodine atom. The term "halogen" represents a chlorine, fluorine, bromine or iodine atom.

In general, various groups or functional groups of variables in the formulas may be optionally substituted with one or more suitable substituents. Examples of substituents are halogen (F, Cl, Br or I), lower alkyl, -OH, -NO 2, -CN, -CO 2 H, lower -O-alkyl, -aryl, -aryl-lower alkyl, -CO ₂ CH 3, -CONH ₂ , OCH ₂ CONH ₂ , -NH ₂ , -SO ₂ NH ₂ , haloalkyl (e.g. -CF ₃ , -CH ₂ CF ₃ ), O-haloalkyl ( e.g. -OCF ₃ , -OCHF ₂ ) and the like.

The terms "comprising" and "including" are used openly, without limitation.

It is understood that although the compound of Formula I may exhibit tautomerism, the figures of the formulas herein deliberately depict only one possible tautomeric form. Thus, it is to be understood that in the invention, the formulas represent each tautomeric form of the depicted compound and are not limited to the specific tautomeric form depicted in the figures of the formulas.

Some of the compounds of the invention may exist as single stereoisomers (i.

substantially free of the other stereoisomer), racemates and / or mixtures of enantiomers and / or diastereomers.

All these individual stereoisomers, racemates and mixtures thereof are included within the scope of the present invention. Preferably, the compounds of the invention that are optically active are used in optically pure form.

As those of ordinary skill in the art will recognize, an optically pure compound having one chiral center is a compound that contains essentially one of two possible enantiomers (i.e., is enantiomerically pure) and an optically pure compound having more than one chiral center is a compound that is pure diastereomerically and pure enantiomerically. Preferably, the compounds of the present invention are used in a form which is at least 90% optically pure, i. in a form comprising at least 90% one isomer (80% enantiomeric excess ("ee") or diastereomeric excess ("de"), more preferably at least 95% (90% ee or de), even more preferably at least 97.5% (95% ee or de) and most preferably at least 99% (98% ee or de).

In addition, solvated, such as, for example, the hydrated formula and solvates include ethanol, methanol, and unsolvated forms are believed to include compounds in the non-hydrated form.

structures in combination with DMSO, ethyl acetate, the formulas indicated cover structures.

designated

Other structures examples with isopropanol, acetic acid or ethanolamine.

In addition to the compounds of formulas I, II, III and IV, the invention includes pharmaceutically acceptable prodrugs, pharmaceutically active metabolites, and pharmaceutically acceptable salts thereof.

"A pharmaceutically acceptable prodrug is a compound that can be converted under physiological conditions or by solvolysis to a specific compound or a pharmaceutically acceptable salt thereof.

"Pharmaceutically active metabolite" means a pharmacologically active product produced by physical metabolism from a specific compound or a salt thereof. The metabolites of the compound can be identified using routine techniques known in the art, and their activities detected using assays, such as those described herein.

Prodrugs and active metabolites of a compound can be identified using routine techniques known in the art. (See, e.g., Bertolini, G. et al., J. Med. Chem., 40, 2011-2016, 1997, Shan, D. et al., J. Pharm. Sci., 86 (7), 765767, Bagshawe K., Drug Dev. Res. 34, 220-230 (1995), Bodor,

N., Advances in Drug Res., 13, 224-331 (1984), Bundgaard, H.,

Design of Prodrugs (Elsevier Press 1985), and Larsen, I. K., Design and Application of Prodrugs, Drug Design and Development, Krogsgaard-Larsen et al., Eds., Harwood Academic Publishers, 1991).

"Pharmaceutically acceptable salt" means a salt that retained the biological activity of the free acids and bases of the specified compounds and which is not biologically or otherwise undesirable. The compound of the invention may have sufficiently acidic, sufficiently basic or both functional groups and accordingly react with any number of inorganic or organic bases and inorganic and organic acids to form a pharmaceutically acceptable salt. Examples of pharmaceutically acceptable salts include salts prepared by reacting the compounds of the present invention with a mineral or organic acid or inorganic base, such as the following: sulfates, pyrosulfates, bisulfates, sulfites, bisulfites, phosphates, monohydrogenphosphates, dihydrogenphosphates, metaphosphates, pyrophosphates, chlorides, bromides , iodides, acetates, propionates, decanoates, caprylates, caproates, succinates, heptanoates, suberates, sebacates, dioates, hexyne-1,6-dioates, propiolates, oxalates, fumarates, maleates, benzoates, dinitrobenzoates, methylbenzoates, methoxybenzoates, phenylacetates, phenylacetates , phenylpropionates, phenylbutyrates, phthalates, naphthalene-2-acrylates, formates, isobutyrates, malonates, butyn-1,4-chlorobenzoates, hydroxybenzoates, xylene sulfonates, citrates, lactates, γ-hydroxybutyrates, glycolates, tartrates, methanesulfonates, propane sulfonates, propane sulfonates, propane sulfonates and mandelates.

When the compound of the invention is a base, the desired pharmaceutically acceptable salt may be prepared by any suitable method available in the art, for example by treating the free base with an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Or an organic acid such as acetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, pyranosidylic acid such as glucuronic acid or galacturonic acid, alpha a hydroxy acid such as citric or tartaric acid, an amino acid such as aspartic acid or glutamic acid, an aromatic acid such as benzoic or cinnamic acid, a sulfonic acid such as p-toluenesulfonic acid or ethanesulfonic acid or the like .

When the compound of the invention is an acid, the desired pharmaceutically acceptable salt may be prepared by any suitable method, for example by treating the free acid with an inorganic or organic base, such as an amine (primary, secondary or tertiary), alkali metal hydroxide or alkaline earth metal hydroxide or the like. Illustrative examples of suitable salts include organic salts derived from amino acids such as glycine and arginine, ammonia, primary, secondary and tertiary amines and cyclic amines such as piperidine, morpholine and piperazine, and inorganic salts derived from sodium, calcium, potassium, magnesium , manganese, iron, copper, zinc, aluminum and lithium.

When the reagents are solids, those skilled in the art will recognize that the compounds and salts of the invention may exist in various crystalline or polymorphic forms, so it is believed that they are all included within the scope of the present invention and the specified formulas.

Therapeutically effective amounts of the agents of the invention can be used to treat diseases mediated by modulation or regulation of protein kinase. "Effective amount" means the amount of agent that when administered to a mammal in need thereof is sufficient to treat a disease mediated by the activity of one or more protein kinases such as tyrosine kinases. So eg. a therapeutically effective amount of a compound of Formula I, a salt, active metabolite or prodrug thereof is an amount sufficient to modulate, regulate, or inhibit the activity of one or more protein kinases such that the disease state mediated by such activity is reduced or ameliorated.

The amount of a given agent that corresponds to that amount varies depending on factors such as the particular compound, the disease state and its, the severity, the identity (e.g., weight) of the mammal in need of treatment, but can still be routinely determined by those skilled in the art. art. The term "treatment" means at least ameliorating a disease state of a mammal, for example a human, which is affected, at least in part, by the activity of one or more protein kinases such as tyrosine kinases, and includes: preventing a disease state in a mammal, particularly when it is found the mammal has a predisposition to the occurrence of a disease state but the disease has not yet been diagnosed, modulating and / or inhibiting the disease state and / or relieving the disease state.

The agents of the invention can be prepared using reactions and synthetic schemes as described below using techniques available in the art and known using starting materials that are readily available.

In one general synthetic process, compounds of Formula I are prepared according to the following reaction schemes:

^ NaOH

2JP0-X

8η0ι

1) I is replaced by M

2) R ² + or

R -M

in n

1) modification

2) -Pg

6-nitroindazole (compound V) was treated with iodine and a base, e.g. NaOH, in an aqueous / organic mixture, with dioxane. The mixture is acidified and the product preferably is isolated by filtration. To the resulting 3-iodo-6-nitroindazole in a mixture of dichloromethane and 50% aqueous KOH at 0 ° C was added a protecting group ("Pg") (where X = halogen), preferably trimethylsilylethoxymethyl chloride (SEM-C1) and a phase transfer catalyst, e.g. tetrabutylammonium bromide (TBABr). After 1-4 hours, the two phases were diluted, the organic layers were separated, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography to give the compound of formula VI. Treatment of compounds of formula VI in a suitable organic solvent with a suitable R ¹ -organometallic reagent, preferably R ¹ -boronic acid, in the presence of an aqueous base, e.g. sodium carbonate, and a suitable catalyst, preferably Pd (PPh 3) 4, gave, after extraction and silica gel chromatography, a compound of formula VII. The R ¹ substituent can be exchanged with compounds of formula VII or later intermediates shown in these schemes by oxidative cleavage (e.g., ozonolysis), followed by addition to the resulting aldehyde functionality by Wittig or condensation transformation (typical examples 42 (ae)). Treatment of the compounds of formula VII with a reducing agent, preferably SnCl 2, yields, after usual aqueous work-up and purification, the compounds of formula VIII. For a variety of derivatives wherein Y = NH or N-lower alkyl, compounds of Formula VIII may be treated with aryl chlorides or heteroaryl chlorides, bromides, iodides or triflates in the presence of a base, preferably Cs ₂ CO 3 and a catalyst, preferably Pd-BINAP, (and Y = N-lower alkyl, followed by an alkylation step) to form compounds of formula X. To form additional Y bonds, sodium nitrite was added to compounds of formula VIII under cooled standard aqueous acidic conditions, followed by addition of potassium iodide and gentle heating. Standard workup and purification gave the iodide compounds of formula IX.

Treatment of compounds of Formula IX with an organometallic reagent, e.g. butyllithium, promotes the exchange of halogen with lithium. This intermediate was reacted with R ² electrophile, e.g. carbonyl or triflate, through possible intermediation by other metals and catalysts, preferably zinc chloride and Pd (PPh ₃ ) ₄ to give compounds of formula X. Alternatively, compounds of formula IX may be treated with an organometallic reagent such as organoboronic acid in the presence of a catalyst, e.g. . Pd (PPh ₃ ) ₄ , in a carbon monoxide atmosphere to form compounds of formula X. Alternatively, for derivatives where Y = NH or S, compounds of formula IX may be treated with suitable amines or thiols in the presence of a base, preferably CS 2 CO 3 or K ₃ PO ₄ and a catalyst, preferably Pd-BINAP or Pd- (biscyclohexyl) biphenylphosphine to form compounds of formula X. Conventional functional group exchanges such as oxidation, reduction, alkylation, acylation, condensation and deprotection can then be used to further derivatize this series for formation of the final compounds of formula I.

Compounds of the invention of formula I may also be prepared according to the general procedure shown in the following scheme:

r’-m catalyst

6-iodoindazole (XI) was treated with iodine and a base, e.g. NaOH, in an aqueous / organic mixture, preferably with dioxane. The mixture is acidified and the product XII is isolated by filtration. To the resulting 3,6-diiodoindazole in a mixture of dichloromethane and 50% aqueous KOH at 0 ° C was added a protecting group agent, preferably SEM-C1, and a phase transfer catalyst, e.g. TBABr. The two phases were diluted, the organic layers were separated, dried over sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography to give the compound of formula XIII. Treatment of compounds of formula XIII in a suitable organic solvent with a suitable R ² -organometallic reagent, e.g. The R ² -ZnCl or boron-R ² -boron reagent, and a suitable catalyst, preferably Pd (PPh ₃ ) _4, gave, after extraction and silica gel chromatography, a compound of formula XIV. Treatment of compounds of formula XIV in a suitable organic solvent with an appropriate R ¹ -organometallic. with an agent (e.g. boron-N-boronic reagent or R 2 ZnCl), in the presence of an aqueous base, sodium carbonate, and a suitable catalyst, preferably Pd (PPh ₃ ) ₄ gave, after extraction and silica gel chromatography, a compound of formula XV. Conventional functional group exchanges such as oxidation, reduction, alkylation, acylation, condensation and deprotection can then be used to further derivatize this series to give the final compounds of formula I.

Alternatively, compounds of formula I wherein R ² is a substituted or unsubstituted Y-Ar, where Y is 0 or S, prepared according to the following general scheme:

MI.XCO-R ¹ jäy xvu

Catalyst, heating or

DDQ modification / θ ' ^R I

A stirred acetone solution of 3-chlorocyclohex-2-enone (XV), HR ² and anhydrous potassium carbonate was heated to reflux for 15-24 hours, cooled and filtered. Concentration and chromatography of the filtrate on silica gel yielded

3-R ² -cyclohex-2-enone (XVI).

The ketones of formula XVI can be reacted with a suitable base (MB), preferably lithium bis (trimethylsilyl) amide, and reacted with a group R ¹ -CO-X (where X = halogen) to yield compounds of formula XVII after standard acid work-up and purification. This product, in a mixture of HOAc and EtQH, mixed with hydrazine monohydrate, was heated at a suitable temperature for a suitable time, preferably at 60-80 ° C for 2-4 hours. After cooling, the mixture was poured into saturated sodium bicarbonate solution, extracted with an organic solvent, concentrated and purified on silica gel to give the compound of formula XVIII.

Compounds of formula XVIII can be oxidized using a number of known methods to give compounds of formula I.

by compound procedures

Other compounds of Formula I may be prepared in analogy to the general procedures described above or detailed in the Examples herein.

according to the invention, many copies of the skeletal ligand provided by the space may be raised to the receptor

Affinity by assuring the use of such interfaces in close proximity, preferably with a carrier group. Multivalent compounds with optimal moieties have been shown to dramatically improve binding to (see, e.g., Lee et al., Biochem, 23, receptor.

Multivalent and spatial

4255, 1984).

the compartments may be selected by selecting suitable carrier units. Such groups include controlled linking groups or molecular carriers that contain a large number of functional groups that can react with functional groups associated with the compounds of the invention. Of course, a wide variety of carriers can be used, including proteins such as BSA or HAS, various peptides such as pentapeptides, decapeptides, pentadecapeptides and the like.

The peptides or proteins may contain the desired number of amino acid residues having free amino groups in their side chains, but other functional groups such as sulfhydryl or hydroxyl groups may also be used to yield stable linkages.

Compounds that potently regulate, modulate or inhibit protein kinase activity associated with VEGF receptors, FGFs, CDK, TEK, CHK1, LCK, FAX and phosphorylase kinase complexes, among others, and which inhibit angiogenesis and / or cell proliferation are desirable and are one preferred Embodiments of the present invention. The present invention further relates to a method of modulating or inhibiting protein kinase activity, for example in mammalian tissue, by administering an agent of the invention. The activity of the compounds of the invention as modulators of protein kinase activity, such as kinase activity, can be measured by any method available to those skilled in the art, including in vivo and / or in vitro assays. Examples of suitable assays for measuring activity include the assays described in Parast C. et al., Biochemistry, 37, 16788-16801, 1998, Jeffrey et al., Nature, 376, 313-320, 1995; WO 97/34876 and WIPO International Patent Application No. WO 96/14843. These properties can be determined, for example, using one or more of the biological testing procedures set forth in the examples below.

The active agents of the invention may be formulated into pharmaceutical compositions as described below. The pharmaceutical compositions of the present invention comprise an effective modulating, regulatory or inhibitory amount of the compounds of Formula I, II, III or IV and an inert, pharmaceutically acceptable carrier or diluent. In one embodiment of the pharmaceutical compositions, effective levels of the agents of the invention are provided to achieve a therapeutically beneficial effect related to the modulation of protein kinases. 'Effective levels are those levels where the effect of protein kinases is regulated to a minimum. These formulations are prepared in unit dosage form suitable for the desired mode of administration, e.g. parenteral or oral administration.

The agent of the invention is administered in the usual dosage form prepared by combining a therapeutically effective amount of the agent (e.g., a compound of formula I) as an active ingredient with suitable pharmaceutical carriers or diluents according to conventional procedures. These processes may include mixing, granulating and compressing, or dissolving the ingredients, as necessary depending on the desired formulation.

Used pharmaceutical liquid. Examples of solid carriers can be either solid or carriers are lactose, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, water and the like.

Similarly, the carrier or diluent may include a time delayed or time controlled release agent known in the art, such as glyceryl monostearate or wax, alone or with glyceryl distearate, namely ethylcellulose, hydroxypropylmethylcellulose, methyl methacrylate and the like.

A variety of pharmaceutical forms can be used. Thus, if a solid carrier has been used, the preparation may be formulated into hard gelatin capsules in the form or tablets, may be placed in powder or pellets, in the form of lozenges or lozenges.

The amount of solid carrier may vary, mg to about 1 g. When in syrup form, but generally from about 25, a liquid carrier, soft gelatin capsule preparation, sterile emulsion solution, injection or suspension in ampoule or vial or a non-aqueous liquid suspension is used.

In order to obtain a stable water-soluble dosage form, the pharmaceutically acceptable salt of an agent of the invention is dissolved in an aqueous solution of an organic or inorganic acid, such as a 0.3M solution of succinic acid or citric acid. If a soluble salt form is not available, the agent may be dissolved in a suitable additional solvent or combination of other solvents. Examples of suitable additional solvents include, but are not limited to, alcohol, propylene glycol, polyethylene glycol 300, polysorbate 80, glycerin and the like. at concentrations ranging from 0 to 60% of the total volume. In an exemplary embodiment, the compound of Formula I was dissolved in DMSO and diluted with water. The composition may also be in the form of a solution of the salt of the active ingredient in a suitable aqueous vehicle, such as water or isotonic saline or dextrose solution.

It is known that the actual doses of the agents used in the compositions of this invention vary according to the particular complex used, the particular formulation formulated, the route of administration and the particular site of administration, the recipient, and the disease being treated. Optimal dosages for a given disease state can be determined by those of skill in the art using conventional dosage determination assays with respect to the experimental data for the agent. For oral administration, an exemplary daily dose generally used is from about 0.001 to about 1000 mg / kg body weight, more preferably from about 0.001 to about 50 mg / kg body weight, with treatment treatments repeated at appropriate intervals. Precursor administrations are typically dosed at weight levels that are chemically equivalent to the weight levels of the fully active form.

The compositions of the invention may be manufactured by methods generally known for the preparation of pharmaceutical compositions, e.g. by conventional techniques such as mixing, dissolving, granulating, draining, levigating, emulsifying, encapsulating, uptake or lyophilizing. The pharmaceutical compositions may be formulated in a conventional manner using one or more physiologically acceptable carriers, which may be selected from the group consisting of excipients and other substances which facilitate processing of the active compounds into preparations which can be used pharmaceutically.

The formulation itself is dependent upon the route of administration selected. For injection, the agents of the invention may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution or saline. For mucosal administration, penetration agents suitable for barrier penetration are used in the formulations. Such penetrating agents are generally known in the art.

For oral administration, the compounds may be readily formulated by combining the active compounds with pharmaceutically acceptable carriers known in the art. Such carriers allow the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, suspensions and the like. for oral ingestion by the treated patient. Pharmaceutical preparations for oral use can be obtained using a solid excipient in admixture with the active ingredient (agent), optionally grinding the resulting mixture and processing the mixture of granules after adding suitable excipients, if desired, to prepare cores for tablets or dragees. Suitable excipients include: fillers, such as carbohydrates, including lactose, sucrose, mannitol, or sorbitol, and cellulosic agents, for example, corn starch, wheat starch, rice starch, potato starch, gelatin, gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose or polyethyl cellulose; (PVP). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar or alginic acid or a salt thereof such as sodium alginate may be added.

Dragee cores are provided with suitable packaging. Concentrated carbohydrate solutions may be used for this purpose, optionally including gum arabic, polyvinylpyrrolidone, Carbopol gel base, polyethylene glycol and / or titanium dioxide, lacquer solution, and suitable organic solvents or solvent mixtures, dyes or pigments may be added to the coatings. tablets or dragees to identify or characterize different combinations of active agents.

Pharmaceutical compositions that can be used orally include push-fit capsules formed from gelatin, as well as soft sealed capsules formed from gelatin and a plasticizer such as glycerol or sorbitol. Push-fit capsules may contain the active ingredients in admixture with fillers such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active agents may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration. For buccal administration, the compositions may take the form of a tablet or lozenge formulated in conventional manner.

For administration by intranasal or inhalation, the compounds for use according to the present invention have usually been formulated in an aerosol spray that is applied from a pressurized pack or nebulizer using a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol package, the unit dose may be determined by using a suitable metering valve to deliver a metered dose. Gelatin capsules and cartridges for use in an inhaler or insufflation apparatus or the like. may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

The compounds may be formulated for parenteral administration by injection, e.g. bolus injection or continuous infusion. Formulations for injection may be presented in unit dosage form, e.g. in ampoules or in multi-dose containers, with added preservatives. The formulations may also take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and / or dispersing agents.

Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. In addition, suspensions of the active agents may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil or synthetic fatty acid esters such as ethyl oleate or triglycerides or liposomes.

Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol or dextran. Optionally, the suspensions may also contain suitable stabilizers or agents which increase the solubility of the compounds to allow the preparation of highly concentrated solutions.

For administration to the eye, the compound of Formula I, II, III or IV is delivered in a pharmaceutically acceptable ophthalmic vehicle, therefore, the compound is maintained in contact with the ocular surface for a sufficient period of time to allow the compound to penetrate the corneal area and inner areas of the eye, including , anterior chamber, posterior chamber, vitreous, aqueous humor, vitreous fluid, cornea, iris / ciliary body, lens, choroid / retina. The pharmaceutically acceptable ophthalmic vehicle may be an ointment, a vegetable oil, or an encapsulant. The compound of the invention may also be injected directly into vitreous humor and aqueous humor.

Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g. sterile pyrogen-free water, just before use. The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g. containing conventional suppository bases such as cocoa butter or other glycerides.

In addition to the formulations described above, the compounds may also be formulated as depot preparations.

Such long acting subcutaneous or intramuscular) or intramuscular formulations may be administered by implantation (for example, by injection. For example, the compounds may be formulated with suitable polymeric or hydrophobic substances (for example, as an emulsion in an acceptable oil) or ion exchange resin or slowly soluble derivatives, for example as a slowly soluble salt.

The pharmaceutical carrier for the hydrophobic compounds is a co-solvent system comprising benzyl alcohol, a non-polar surfactant, a water-miscible organic polymer and an aqueous phase. The additional solvent system may be a VPD system of additional solvents. VPD is a solution of 3% (w / v) benzyl alcohol, 8% (w / v) non-polar polysorbate 80 surfactant and 65% (w / v) polyethylene glycol 300, made up to volume with absolute ethanol. The VPD system of additional solvents (VPD: 5W) contains VPD diluted 1: 1 with 5% dextrose in water. This additional solvent system dissolves well the hydrophobic compounds and is itself of low toxicity after systemic administration. Naturally, the ratio of the other solvent system can be varied considerably without compromising its characteristic solubility and toxicity. In addition, the identity of the constituents of the other solvent system may be altered: for example, other nonpolar, low toxicity surfactants may be used instead of polysorbate 80, the fraction size of the polyethylene glycol may be changed, other biocompatible polymers may replace polyethylene glycol, e.g. the polyvinylpyrrolidone and the dextrose may be substituted with other saccharides or polysaccharides.

Alternatively, other delivery systems may be used for the hydrophobic pharmaceutical compounds. Liposomes and emulsions are known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents, such as dimethylsulfoxide, may also be used, although usually at the cost of greater toxicity. In addition, the compounds may be administered using a sustained release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials known to those skilled in the art have also been introduced. Prolonged-release capsules may, depending on their chemical nature, release the compounds for several weeks to 100 days. Depending on the chemical nature and biological stability of the therapeutic agent, further strategies may be used to stabilize the protein.

The pharmaceutical preparations may also contain suitable solid or gel carriers or excipients. Examples of such carriers or excipients include calcium carbonate, calcium phosphate, carbohydrates, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.

Some of the compounds of the invention may be provided as salts with pharmaceutically compatible counterions (counterions). Pharmaceutically compatible salts can be formed with many acids, including hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, and the like. The salts tend to be more soluble in aqueous or other proton solvents than the corresponding free base forms.

The preparation of preferred compounds of the present invention is described in detail in the following examples, but one skilled in the art will recognize that the described chemical reactions can be readily modified to prepare a variety of other protein kinase inhibitors of the invention. For example, the synthesis of compounds of the invention that are not exemplified in the examples can be successfully performed by modification known to those skilled in the art, e.g. using appropriate protection for interfering groups, exchanging suitable reagents known in the art, or making routine modifications to the reaction conditions. Alternatively, other reactions described herein or known in the art are considered useful for preparing other compounds of the invention.

Examples

In the examples described below, unless otherwise indicated, all temperatures are in degrees Celsius and all parts and percentages are by weight. Reagents were purchased from commercial suppliers such as Aldrich Chemical Company or Lancaster Synthesis Ltd. and were used without further purification unless otherwise noted. Tetrahydrofuran (THF), N, N-dimethylformamide (DMF), dichloromethane, toluene and dioxane were purchased from Aldrich in sealed bottles and used immediately upon receipt. All solvents were purified using standard methods known to those skilled in the art, unless otherwise indicated.

The reactions listed below were generally performed under argon or nitrogen overpressure or with test tube drying, at room temperature (unless otherwise specified) in anhydrous solvents, and the reaction flasks were sealed with rubber trays for introducing substrates and reagents via a syringe. The chemical glass was oven-dried and / or heated. Analytical thin layer chromatography (TLC) was carried out on heat-treated glass plates with 60 F 254 Analtech silica gel (0.25 mm) and eluted with appropriate solvent (v / v) ratios and indicated at the appropriate location. The reactions were tested by TLC and terminated after it was judged that the starting material was consumed.

Visualization of TLC plates was performed by spraying with p-anisaldehyde reagent or phosphomolybdenoic acid (Aldrich Chemical 20% (w / w) in ethanol) and activation by heating. Treatment was typically performed by doubling the reaction volume with the reaction solvent or extraction solvent, and then washing with said aqueous solutions using 25% volume of the extraction volume unless otherwise indicated. The product solutions were dried over anhydrous Na ₂ SO ₄ before filtering and evaporating the solvents under reduced pressure on a rotary evaporator, then it was reported that the solvents were removed in vacuo. Flash column chromatography (Still et al., J. Org. Chem., 43, 2923 1978) was performed using silica gel for flash chromatography (47-61 μιη, Baker) and silica gel: crude material ratio about 20: 1 to 50: 1 unless otherwise noted. The hydrogenolysis was carried out at the pressure given in the examples or at ambient pressure.

¹ H-NMR spectra were recorded on a Bruker instrument operating at 300 MHz and ¹³ C-NMR spectra were recorded at 75 MHz. NMR spectra were obtained as CDCl ₃ solutions (reported in ppm), using chloroform as the reference standard (7.25 ppm and 77.00 ppm) or CD ₃ OD (3.4 and 4.8 ppm and 49.3 ppm, respectively). or internally tetramethylsilane (0.00 ppm) where necessary. Additional NMR solvents were used as needed. Where multiple peaks are given, the following abbreviations have been used: s (singlet), d (doublet), t (triplet), m (multiplet), w (broad), dd (doublet of doublets), dt (doublet of triplets). Where condensation constants are given, they are in units of Hertz (Hz).

Infrared (IR) spectra were recorded on a Perkin-Elmer FT-IR spectrometer for pure oils, as KBr pellets or as CDCl 3 solutions, and are reported in wavelength (cm ^-1 ) where indicated. Mass spectra were obtained using LSIMS or electrospray method. All melting points (tt) were uncorrected.

Example 1 (a)

3- [E-2- (3,4-dimethoxyphenyl) vinyl] -6- (3-methoxy-4-hydroxyphenyl) -1H-indazole ~ 205 mg (0.461 mmol) (theoretical) 3- [E / Z-2- (3,4-Dimethoxyphenyl) vinyl] -6- [3-methoxy-4- (methoxymethoxy) phenyl] -1 -indazole was dissolved in 10 mL tetrahydrofuran (THF) and treated with 10 mL water and 20 mL trifluoroacetic acid (TFA). The reaction mixture was left under stirring at 23 ° C for 30 minutes. The mixture was diluted with 100 mL of toluene and the volatiles were removed under reduced pressure (30 mm Hg, 35 ° C) to give a concentrated volume of 55 mL. Again, 100 mL of toluene was added and the mixture was concentrated under reduced pressure to give a crude which still contained some acid. Partition between ethyl acetate and saturated sodium bicarbonate, separate the organic, dry over sodium sulfate, decant and concentrate under reduced pressure. ~ 185 mg (0.461 mmol) (theoretically) of the residue, a mixture of olefinic isomers, was taken up in 50 ml of dichloromethane at 23 ° C and treated with 80 mg of iodine. The mixture was left under stirring at 23 ° C for 12 hours. The mixture was treated with 10 mL of saturated sodium bicarbonate with 10 mL and 5% aqueous sodium bisulfite. The mixture was diluted with 200 mL ethyl acetate and the organic was washed with 100 mL saturated sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure to give the crude product. The crude product was purified on 40 mL silica gel (ethyl acetate / hexane)

6: 4 -> 7: 3) and all fractions containing the desired product were combined, concentrated and precipitated from the dichloromethane / hexane bilayer (1: 3) to give 93 mg (combined yields) of 3- [E-2- (3,4) dimethoxyphenyl) -vinyl] -6- (3-methoxy-4-hydroxyphenyl) ΙΗ-indazole as a white solid: R _f sm 0.42, p 0.35 (ethyl acetate-hexane 7: 3), FTIR (thin film ) 3324, 1600, 1514, 1463, 1422, 1264, 1137, 1024, 959, 852 cm ¹ , ¹ H NMR (CDCl ₃ ) δ

10.0 (bs, 1H), 8.08 (d, 1H, J = 8.4 Hz), 7.59 (s, 1H), 7.49 (d, 1H, J = 16.6 Hz) 7.45 (dd, 1H, J = 1.4, 8.4 Hz), 7.34 (d,

1H, J = 16.6Hz), 7.20-7.12 (m, 4H), 7.03 (d, 1H, J = 8.0Hz),

6.91 (d, 1H, J = 8.2 Hz), 5.68 (bs, 1H), 3.99 (s, 3H), 3.97 (s, 3H), 3.93 (s, 3H), ¹³ C NMR (CDCl 3) δ 149.6, 149.5, 146.0,

144.0, 142.6, 140.8, 133.9, 131.4, 130.7, 121.7, 121.4, 120.9, 120, 4, 120.2, 118, 6, 115, 4, 111.7, 110.8, 109, 1, 108, 2, 56, 4,

56.3, 56.2. HRMS (ES) [M + H] / z calc. 403.1658, measured

403.1658. [M-H] / z calcd. 401, measured 401.

The starting material was prepared as follows:

(I)

NaNO 3, HCl ΚΙ, H 2 O 0 to 50 ° C

To 40.8 g (0, 3065 mol, 1 eq.) Of 6-aminoindazole in a 2 L round bottom flask (2 L) containing a large magnetic stirrer was added 256 g of ice followed by 128 mL of water and the reaction vessel was immersed in an ice bath. To this stirred suspension at 0 ° C was added 128 mL (1.53 mol, 5 eq) of concentrated aqueous HCl. Then, 23.3 g (0.338 mol, 1.1 eq.) Of a solution of NaNO ₂ in 96 mL of water was added. After stirring at 0 ° C for 10 minutes, 61 g (0.368 mol, 1.2 eq.) Was added to the KI initially very slowly (~ 100 mg at a time, since the first small doses of KI cause rapid gas evolution) and then faster (total). 5 minutes). The cold bath was removed and the reaction mixture was heated to 40 ° C (evolution of gas). When the gas evolution rate decreased (~ 30 minutes), the reaction mixture was heated to 50 ° C for 30 minutes. The mixture was then cooled to 23 ° C and 320 mL of 3N NaOH was added to neutralize, followed by 320 mL of 50% saturated NaHCO 3. The suspension was then filtered through a Buchner funnel to give a dark red-brown solid. The solid was taken up in 800 mL of heated THF and 600 mL of dry silica gel was added with stirring. To this suspension was added 1.2 L of hexane and the mixture was vacuum filtered through a short column of 300 mL silica gel in a large fritted filter. The silica gel was further washed with 2 L of 40% THF in hexane. The filtrates were combined and concentrated under reduced pressure to give a solid. The solid was further triturated with ~ 100 mL of ethyl acetate, filtered, and dried under reduced pressure to give 36.1 g (48% yield) of 6-iodo-1H-indazole as a light brown solid: R _f

sm 0.12, p 0.48 (CDCl ₃ ) 7.9 (s, 1H), 7.8 (ES) [M + H] / z calcd 243, measured 243. hexane and EtOAc 1: 1), ¹ H NMR (300 MHz, (s, 1H), 7.42 (d, 1H), 7.33 (d, 1H), MS 245, measured 245, [MH] / z calculated ώ £ τ NaO-tBu, MtoCl, THF, 0 * 0.40 min ------ ► ΐοτ

(Ii)

To a solution of 7.35 g (30.1 mmol, 1 eq.) Of 6-iodo-1H-indazole in 100 mL of THF cooled to 0 ° C under argon was added 2.89 g (30.1 mmol, 1 eq.). sodium t-butoxide. A change in color from orange to red was observed. 6.60 g (30.1 mmol, 1 eq) of mesitylenesulfonyl chloride was added in one portion and the ice bath was removed and the reaction mixture was allowed to warm to 23 ° C. After 40 minutes, the mixture was quenched with saturated ammonium chloride and partitioned between water and ethyl acetate. The aqueous layer was extracted a total of 3 times with ethyl acetate. The combined organics were washed with brine, dried over sodium sulfate and concentrated under reduced pressure to give 12.8 g (100% yield, 2: 1 mixture) of 6-iodo-1- (2,4,6-trimethylbenzenesulfonyl) -1H-indazole as a orange solid. ¹ H NMR (CDCl 3) δ, 51 (s, 1H), 7.95 (s, 0.66H, major isomer),

7.91 (s, 0.33H, minor isomer), 7.47 (d, 0.33H, J = 8.4 Hz), 7.29 (d, 0.33H, J = 8.4 Hz), 7.26 (d, 0.66H, J = 8.9 Hz), 7.18 (d, 0.66H, 8.9 Hz), 6.84 (s, 2H), 2.51 (s, 6H) 2.15 (s, 3H).

(Iii)

A mixture of 5.78 g (13.56 mmol, 1.00 eq) of 6-iodo-1- (2,4,6-trimethylbenzenesulfonyl) -ΙΗ-indazole and 3.45 g (16.27 mmol, 1.20)

3-Methoxy-4- (methoxymethoxy) benzeneboronic acid under argon was dissolved in 15 mL dioxane and 2.0 mL water. To this solution were added 2.83 mL (20.3 mmol, 1.5 eq.) Triethylamine, 2.8 g (20.3 mmol, 1.5 eq.) Potassium carbonate, and 476 mg (0.678 mmol, 0. 05 eq) dichlorobis (triphenylphosphine) palladium. The reaction mixture was heated at 90 ° C for 2 hours, and then cooled to 23 ° C. The mixture was partitioned between 250 mL of ethyl acetate and 150 mL of saturated sodium bicarbonate. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure to give crude 6- (3-methoxy-4-methoxymethoxyphenyl) -1 (2,4,6-trimethylbenzenesulfonyl) -ΙΗ-indazole, which was dried under high vacuum. for 15 hours and was used without further purification.

3-Methoxy-4- (methoxymethoxy) benzeneboronic acid was prepared as follows: in a 100 mL flask, a mixture of 50% KOH in water (20 g KOH, 7 eq., 20 g ice) was prepared under an argon atmosphere. To this rapidly stirred mixture at 0 ° C (maintained in an ice bath) was added 50 mL of dichloromethane, followed by 10.1 g (50 mmol, 1.00 eq.)

4-bromo-2-methoxyphenol, 4.00 mL (42.5 mmol, 1.05 eq) methoxymethyl chloride (MOMCl) and 322 mg (1 mmol, 0.02 eq) tetrabutylammonium bromide. The bath was removed and the mixture was allowed to warm slowly to 23 ° C with rapid stirring for 2 hours. The mixture was transferred to a separatory funnel and ordered with 350 mL of dichloromethane and 300 mL of water, which are used to facilitate transfer. The organic (now lower layer) was separated, dried over sodium sulfate, decanted and concentrated under reduced pressure to give 11.9 g (97%).

4-bromo-2-methoxy-l- (methoxymethoxy) benzene as a yellow liquid which was purified by ^X H NMR: ¹ H NMR (CDC1 ₃₎ δ 7.0 (s, 3H), 5.13 (s, 2H ), 3.84 (s, 3H), 3.47 (s, 3H). MS (EI) [M + H] / z calc'd 235, measured 235. A 50 mL round bottom flask was charged with 4.80 g (19.4 mmol, 1.00 equiv) of 4-bromo-2-methoxy- Of 1- (methoxymethoxy) benzene in 35 mL of THF and cooled to -78 ° C (20 minutes for this volume). To this mixture was added 12.75 mL of 1.6 M in hexane (20.4 mmol, 1.05 eq.) N-BuLi and the mixture was allowed to stir at -78 ° C for 40 minutes. The mixture was then added via cannula to a second flask containing 22 mL (194 mmol, 10 eq) of B (OMe) _{3 in} 50 mL of THF at -78 ° C. After 20 minutes, the cold bath was removed. After heating for 15 minutes (°0 ° C, ice on the side of the flask began to melt) 50 mL of water was added to the reaction mixture, which was stirred for 45 minutes. The mixture was concentrated under reduced pressure to remove most of the THF, and then partitioned between 300 mL of ethyl acetate and 150 mL of water, which was acidified by the addition of a small amount, 1010 mL, of 20% citric acid. The organic was dried over sodium sulfate and concentrated under reduced pressure to give a solid. Trituration with 10 mL of ethyl acetate and 5 mL of hexane followed by filtration afforded 3.15 g (77%) of 3-methoxy-4- (methoxymethoxy) benzeneboronic acid as a white solid: Rf sm 0.59, p 0.18 (ethyl acetate / hexane mixture)

1: ^1): 1 HNMR (CDCl ₃₎ δ 7.85 (d, 1Η, J = 8 Hz), 7.72 (s, 1H).

7.22 (d, 1H, J = 8Hz), 5.30 (s, 2H), 4.00 (s, 3H), 3.55 (s, 3H).

(Iv)

Unpurified 6- (3-methoxy-4-methoxymethoxyphenyl) -1- (2,4,6-trimethylbenzenesulfonyl) -ΙΗ-indazole (under argon atmosphere) was dissolved in 20 mL THF and treated with 70 mL IN NaOH in MeOH (affected by bubbling) via argon for 3 to 5 minutes). The mixture was heated to 45 ° C for 1 hour and allowed to cool. The mixture was neutralized by the addition of 50 mL of 1N HCl, followed by 200 mL of saturated sodium bicarbonate. The product was extracted with 350 mL ethyl acetate, dried over sodium sulfate, and concentrated under reduced pressure to give crude 6- (3-methoxy-4-methoxymethoxyphenyl) -1H-indazole. Purification by silica gel chromatography (500 ml silica gel,

1.8 L of 20% ethyl acetate in benzene, 1.8 L of 30% ethyl acetate in benzene) gave 1.19 g (31%) of 6- (3-methoxy-4-methoxymethoxyphenyl) -ΙΗ-indazole: ¹ H NMR (CDCl 3) δ 7.80 (s, 1H), 7.69 (d, 1H, J = 8.5 Hz), 7.52 (s, 1H), 7.29 (d, 1H, J = 8.5) Hz), 7.16 (s, 1H), 7.13 (s, 1H), 7.08 (s, 1H). MS (ES) [m + Na] / z calcd 337, measured 337, [m + Cl] / z, calcd 349, measured

349th

Ij. NaOH, Cdioxane

23-0,1 h

(in)

In a 100 mL round bottom flask under argon, 1.19 g (4.18 mmol, 1 eq) of 6- (3-methoxy-4-methoxymethoxyphenyl) -1H-indazole were dissolved in 25 mL of dioxane and 14 mL of 3N NaOH . This mixture was treated with 1.17 g (14.60 mmol, 1.10 eq) of iodine added in ~ 5 portions (~ 10 minutes). Several additional portions of (~ 4) iodine of 50 mg were added until the reaction was complete as visualized by TLC (3: 7 ethyl acetate / hexane). The mixture was acidified with 25 mL of 20% citric acid and 20 mL of 5% NaHSO ₃ was added. The mixture was partitioned between 150 mL of ethyl acetate and 100 mL of water. The organic was washed with 80 mL saturated sodium bicarbonate and 50 mL brine, and dried over sodium sulfate and concentrated under reduced pressure. Purification by crystallization from 3 mL of ethyl acetate and then 7 mL of hexane gave 1.33 g (78%) of pure 3-iodo-6- (3-methoxy-4-methoxymethoxyphenyl) -ΙΗ-indazole as a solid: ¹ H NMR (CDCl ₃ ) δ 10.48 (bs, 1H), 7.62 (s, 1H), 7.57 (d, 1H, J = 8.5 Hz), 7.47 (dd, 1H, J = 1.3), 8.5 Hz), 7.18 (m, 3H), 5.29 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).

In a 100 mL round bottom flask, 921 mg (2.245 mmol, 1.00 eq) of 3-iodo-6- (3-methoxy-4-methoxymethoxyphenyl) -ΙΗ-indazole was dissolved in 36 mL of THF and cooled to - 78 ° C (8 minutes left). 2.5 mL of a 1.8 M solution (4.49 mmol, 2.00 eq) of PhLi was added and the mixture was allowed to stir for 30 minutes. 3.63 mL (4.71 mmol, 2.1 eq) of s-BuLi solution was added and the reaction mixture was allowed to stir at -78 ° C for 1 h. 1.4 mL (18 mmol, 8.0 eq.) Of pure DMF was added. The cold bath was removed and the reaction allowed to warm slowly to 0 ° C in air. When ice was melting, 20 ml of saturated sodium bicarbonate was added. The product was extracted with 200 mL of ethyl acetate from an additional 75 mL of saturated sodium bicarbonate, dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (450 mL silica gel, ethyl acetate / hexane 4: 6) gave 498 mg (71%) of 6- (3-methoxy-4-methoxymethoxyphenyl) -1H-indazole-3-carbaldehyde: R f sm 0.30, p 0.14 (4: 6 ethyl acetate / hexane), ¹ H NMR (CDCl ₃ ) δ 10.85 (bs, 1H), 10.25 (s, 1H), 8.37 (d, 1H, J = 8.4. Hz), 7.67 (s, 1H), 7.60 (d, 1H, J = 8.4 Hz), 6.26 (d, 1H, J = 8.7 Hz), 7 19 (m, 2H), 5.30 (s, 2H), 3.99 (s, 3H), 3.55 (s, 3H).

(Vii)

441 mg (1.41 mmol, 1.0 eq.) Of 6- (3-methoxy-4-methoxymethoxyphenyl) -1H-indazole-3-carbaldehyde was taken as a slurry into 15 mL of dichloromethane and cooled to 0 ° C. This mixture was treated with 324 mg (1.48 mmol, 1.05 eq) of mesitylenesulfonyl chloride and 181 mg (1.48 mmol, 1.05 eq) of dimethylaminopyridine (DMAP). The mixture was allowed to stir at 0 ° C for 1 hour and quenched by the addition of water. The mixture was partitioned between water and an organic layer of a 1: 1 mixture of ethyl acetate and hexane. The organic was dried over sodium sulfate, decanted, and concentrated under reduced pressure to give a crude which was purified by silica gel chromatography (50 mL silica gel, ethyl acetate / hexane 3: 7) to give 374 mg (54%) of 6- (3). methoxy-4-methoxymethoxyphenyl) -1- (2,4,6-trimethylbenzenesulfonyl) -1H-indazole-3-carbaldehyde: R _f 0.17, p 0.53 (4: 6 ethyl acetate / hexane), ³ H NMR (CDC1 ₃₎ δ 10.20 (s, 1H), 8.41 (s, 1H), 8.37 (d, 1 H, J = 8.5 Hz), 7.73 (dd, 1 H, J = 1 4, 8.4 Hz), 7.3 (m, 3H), 7.08 (s, 2H), 5.36 (s, 2H), 4.08 (s, 3H), 3.71 (s 3H), 2.74 (s, 6H), 2.40 (s, 3H).

(Viii)

1.09 g (2.22 mmol, 4.0 eq.) Of finely ground triphenyl (3,4-dimethoxybenzyl) phosphonium bromide was taken as a slurry into 15 mL of THF and cooled to -78 ° C. To this mixture was added 1.04 mL of 1.6M (1.66 mmol, 3.0 eq) n-BuLi to give a red-orange solution. The mixture was allowed to warm to 23 ° C for 1 hour. This mixture was then added via cannula to a solution of 274 mg (0.554 mmol, 1.0 eq) of 6- (3-methoxy-4-methoxymethoxyphenyl) -1- (2,4,6-trimethylbenzenesulfonyl) -1H- indazole-3-carbaldehyde in 5 mL THF. The resulting mixture was allowed to stir at 0 ° C for 10 minutes and was quenched with saturated sodium bicarbonate. The resulting mixture was partitioned between saturated sodium bicarbonate and ethyl acetate. The organic was concentrated under reduced pressure and the residue was purified by silica gel chromatography (50 mL silica gel, ethyl acetate / hexane 3: 7-> 4: 6) to give 289 mg (83%) of a 2.5: 1 cis / trans 3 mixture. - (2- (3,4-dimethoxyphenyl) vinyl) -6- (3-methoxy-4-methoxymethoxyphenyl) -1 (2,4,6-trimethylbenzenesulfonyl) -ΙΗ-indazole: R _f 0.53, p 0.32 (ethyl acetate / hexane 4: 6), ¹ H NMR (CDCl ₃ ) δ 8.35 (s,

0.3H), 8.32 (s, 0.7H), 8.03 (d, 0.3H, J = 8.4 Hz), 6.60-6.85 (m, H), 6.65 (d, 0.7H, J 8.4 Hz), 6.60 (d, 0.7H, J = 12.5 Hz),

5.30 (s, 0.6H), 5.29 (s, 1.4H), 4.00-3.50 (8 singlets, 12H),

2.72 (s, 1.8H), 2.67 (s, 4.2H), 2.34 (s, 3H), MS (ES) [M + H] / z calcd 629, found 629, [MH] ] / z calcd. 627, measured

627th

(Ix)

A solution of 1.0 g (17.8 mmol) of 1M KOH in water: MeOH (18 mL in total) was prepared under an argon atmosphere and degassed by vacuum / argon cycles (5 times). In a separate flask was dissolved 289 mg (0.461 mmol, 1.0 eq) of 3- [2- (3,4-dimethoxyphenyl) vinyl] -6- (3-methoxy-4-methoxymethoxyphenyl) -1 (2,4,6- trimethylbenzenesulfonyl) -ΙΗ-indazole in 8 mL of THF under argon. To this solution was added 10 mL of the above 1M KOH solution in water / MeOH 1: 1. The reaction was warmed to 30 ° C and left under stirring for 7 hours. The reaction mixture was neutralized by adding 7 ml of 20% citric acid. The resulting mixture was partitioned between 150 mL ethyl acetate and 100 mL water. The organic was separated, dried over sodium sulfate, decanted and concentrated under reduced pressure to give cis and trans 3- [2- (3,4-dimethoxyphenyl) vinyl] -6- (3-methoxy-4-methoxymethoxyphenyl) -1H-indazole ( crude product used): Rf sm 0.46, p1 0.17, p2 0.23 (1: 1 ethyl acetate-hexane), ² H NMR cis isomer (CDCl ₃ ) δ

7.55 (s, 1H), 7.3-7.1 (m, 6H), 7.02 (dd, 1 H, J = 1.9. 8, 3 Hz), 6.85 (d, 1H, J = 12.5 Hz), 6.78 ( d. 1H, J = 12.5 Hz), 6, 74 (D, 1 H, J = 8.3 Hz), 5.21 (s, 2H), 3 88 (s. 3H), 3.70 (WITH, 3H),

3.43 (s, 3H); 3.42 (s, 3H). MS (ES) [M + H] / z calc. 447, measured 447, [M-H] / z calc. 445, measured 445.

Example 1 (b)

3- (E-styryl) -6- (3-benzyloxy-4-hydroxyphenyl) -lH-indazole

The compound of Example 1 (b) was prepared in a similar manner to that described in Example 1 (a) except that

4-Bromo-2-benzyloxyphenol was used in step (iii) instead

4-bromo-2-methoxyphenol. R f sm 0.35, p 0.30 (ethyl acetate-hexane 4: 6), NMR (CDC1 ₃₎ δ 8.06 (d, 1 H, J = 8.6 Hz), 7,637,18 (m, 17 H) 7.05 (d, 1H, J = 8.2Hz), 5.19 (s, 2H). MS (Cn [M + H] / z calc. 419, measured 419, [MH] / z calc. 417, measured 417.

Example 1 (c)

3- [E-2- (3,4-dimethoxyphenyl) -vinyl] -6- (3-allyloxy-4-hydroxyphenyl) -lH-indazole

The compound of Example 1 (c) was prepared in a similar manner to that described in Example 1 (a) except that 3-allyloxy-4- (methoxymethoxy) benzeneboronic acid was used in place of 3-methoxy-4- (methoxymethoxy) benzeneboronic acid. in step (iii). MS (ESI) [M + H] / z calcd 429, found 429, MS (ESI) (M-H] / z calcd 427, measured 427.

Example 2 (a)

3- (Naphthalen-2-yl) -6- (3-methoxy-4-hydroxyphenyl) -1H-indazole mg (0.055 mmol) 6- (4-benzyloxy-3-methoxyphenyl) -3-naphthalen-2-yl-1H- indazole was dissolved in a mixture of 2 ml of ethyl acetate, 2 ml of benzene and 2 ml of methanol. To this solution was added 25 mg of 10% (w / w) palladium on carbon and the reaction vessel was degassed by vacuum / hydrogen cycles (five cycles). The reaction mixture was left under stirring for 3 days at 23 ° C and filtered through a short column of celite. Concentration and purification by silica gel chromatography gave 8 mg (40%) of 3- (naphthalen-2-yl) -6- (3-methoxy-4-hydroxyphenyl) -1H-indazole: NMR (CDCl ₃ ) δ 10.3 (bs, 1H )

8.50 (s, 1H), 8.20 (d, 1H, J = 8Hz), 7.98 (d, 1H, J = 8Hz), 7.90 (m, 1H), 7.7- 6.8 (m, 9H); 3.98 (s, 3H). MS (ES) [M + H] / z calc. 367, measured 367, [M-H] / z calc. 365, measured

365th

The starting material was prepared as follows:

(i). M (PPfX) * TKF

117 mg (0.564 mmol, 6.0 eq.) Of 2-bromonaphthalene was dissolved in 0.75 mL of THF and cooled to -78 ° C. The mixture was treated with 226 μΐ 2.5M (6.0 eq) n-BuLi and left under stirring at -78 ° C for 30 minutes. The mixture was then added via cannula to 139 mg (0.80 mmol, 8.5 eq) of freshly dried solid ZnCl ₂ and the resulting mixture was allowed to warm to 23 ° C (the yellow color disappeared during the addition). After 30 minutes at 23 ° C, the mixture was added via cannula to a mixture of 60 mg (0.094 mmol, 1 eq.) Of 6- (4-benzyloxy-3-methoxyphenyl) -3-iodo-1 (2,4,6-trimethylbenzenesulfonyl) - Ind-indazole and 6 mg (0.005 mmol, 0.05 eq.) Of Pd (PPh ₃ ) ₄ . The resulting solution was left under stirring for 16 hours. Saturated sodium bicarbonate was added and the mixture was partitioned between 15 mL saturated sodium bicarbonate and 15 mL ethyl acetate. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (ethyl acetate / hexane 1: 9-2: 8) gave 42 mg (70%) of 6- (4-benzyloxy-3-methoxyphenyl) -3-naphthalen-2-yl-1- (2,4,6) -trimetylbenzénsulfonyl) -ΙΗ-indazole as a solid: R f sm 0.4, p 0.4 (ethyl acetate: hexane 3: ^7): 1 HNMR (CDCl ₃₎ δ 8.44 (s, 1H), 8, 41 (s, 1H), 8.12 (d, 1H, J = 8Hz), 8.05-7.00 (m, 17H), 5.30 (s, 2H), 4.02 (s, 3H) 1.80 (s, 3H), 2.34 (s, 3H).

6- (4-Benzyloxy-3-methoxyphenyl) -3-iodo-1- (2,4,6-trimethylbenzenesulfonyl) -1H-indazole was prepared in a manner similar to that described in Example 1 (a), steps (i) to (v).

(Ii)

6- (4-Benzyloxy-3-methoxyphenyl) -3-naphthalen-2-yl-1- (2,4,6-trimethylbenzenesulfonyl) -4-indazole was converted to 6- (4-benzyloxy-3-methoxyphenyl) -3-naphthalene- 2-yl-1H-indazole as was

described in Example 1 (a) step (Ix) . Rf sm 0.40, After , 17 (a mixture of ethyl acetate and hexane 3: 7), ^X 1 HNMR (CDCl ₃₎ δ 8.40 (with, 1H), 8.12 (D, 1H, J = 8.5 Hz), 8.10 (Dd, 1H, J = 1.6, 8.4 Hz), 7.93 (d, 1H, J = 8.3 Hz), 7.88 (m, 2H), 7, 61 (m, 1H) 7.56 (with, 1H), 7.43 (M, 5H), 7.30 (m 3 H), 7.15 (d, 1H, J = 2.0 Hz), 7.08 (d , 1H, J = 2.1, 8.3 Hz), 6.91 (d, 1H, J = 8.3 Hz), 5.16 (with, 2H), 3, 91

(s, 3 H).

Example 2 (b)

3-phenyl-6- (3-methoxy-4-hydroxyphenyl) -lH-indazole

The compound of Example 2 (b) was prepared in a similar manner to that described in Example 2 (a) except that phenyllithium was used instead of 2-naphthyllithium formed from 2-bromonaphthylene in step (i). ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.87 (d,

1H), 7.83 (d, 2H), 7.55-7.27 (m, 5H), 7.01 (m, 2H), 6.80 (d, 1H), 3.83 (s, 3H) ). MS (ES) [M + H] / z calc. 317, measured 317, [M-H] / z calc. 315, measured 315.

Example 2 (c)

3- (3,4,5-trimethoxyphenyl) -6- (3-methoxy-4-hydroxyphenyl) -lH-indazole

The compound of Example 2 (c) was prepared in a similar manner to that described in Example 2 (a) except that instead of

3,4,5-trimethoxyphenyl bromide was used in step (i)

2-brómnaftylénu. Rf sm 0.67, p 0.38 (ethyl acetate / hexane)

8: 2), ^X H NMR (CDCI ₃ : ) δ 7.93 (D, 1 H, J = 8 Hz), 7.58 (s, 1H) 7, 39 (D, 1H, J = 8 Hz), 7.10 (M, 4H), 6.92 (d, 1 H, J = 8) Hz) 3, 90 (with, 9H) , 3.85 (s, 3H) MS (ES) [M + H] / z calcd 407

found407, [M-H] / z calcd 405, found 405.

Example 2 (d)

3- (lH-indol-2-yl) -6- (3-methoxy-4-hydroxyphenyl) -lH-indazole

The compound of Example 2 (d) was prepared in a similar manner to that described in Example 2 (a) above, except that 1-phenylsulfonylindazole was used in place of 2-bromonaphthylene in step (i). R _f sm 0.20, p 0.15 (ethyl acetate-hexane 4: 6), ^X 1 HNMR (CDCl ₃₎ δ 10.0 (br s, 1H), 9.05 (br s, 1H), 8 Δ (d, 1H, J = 8.0 Hz), 7.55 (d, 1H, J = 8.0 Hz), 7.49 (s, 1H), 7.37 (d, 1H, J = 8 Hz), 7.29 (d, 1H, J = 8 Hz), 7.2-7.1 (m, 5H), 6.92 (d, 1H, J = 8 Hz), 5.63 (b) s, 1H), MS (ES) [M + H] / z calc 356, measured 356, [MH] / z calc 354, measured 354.

Example 2 (e)

3- (benzofuran-2-yl) -6- (3-benzyloxy-4-hydroxyphenyl) -lH-indazole

The compound of Example 2 (e) was prepared in a similar manner to that described in Example 2 (a) above except that benzofuran was used instead of 2-bromonaphthylene in step (i). ^X 1 HNMR (CDCl ₃₎ δ 8.21 (d, 1 H, J = 8.0 Hz), 7.60 (m, 3H), 7.30-7.10 (m, 12H), 7.01 ( d, 1H, J = 8 Hz), 5.82 (bs, 1H), 5.15 (s, 3H).

Example 3

3- (lH-indol-2-yl) -6- (3-methoxy-4-hydroxyphenyl) -lH-indazole

3- (1H-benzimidazol-2-yl) -6- (3-methoxy-4-methoxymethoxyphenyl) -1H-indazole was converted to 3.5 mg (28%) of 4- [3- (1H-benzimidazol-2-yl) - 1H-indazol-6-yl] -2-methoxyphenol according to the procedure described in Example 1 (a). HRMS (FAB) [M + H] / z calc. 357.1351, found 357.1349.

The starting material was prepared as follows:

CC

CuAc> AcOH ΜΟΗ, Η Ο Ο

mg (0.064 mmol, 1 eq.) of 6- (3-methoxy-4-methoxymethoxyphenyl) -1H-indazole-3-carbaldehyde (from Example 1 (a), step (vi)) was dissolved in 0.7 mL of degassed mixture MeOH and water 1: 1 and treated with 19 μΐ (5 eq.) Of acetic acid, 8.3 mg (1.2 eq.) Of 1,2-diaminobenzene and 18 mg (1.4 eq.) Of copper acetate in 23 C. The mixture was stirred for 30 minutes, diluted with 3 mL of ethanol and 2 mL of water, and subjected to bubbling with a stream of SH ₂ for 3 minutes to give a black precipitate. The mixture was left under stirring for 12 hours. The mixture was filtered and concentrated. Purification by silica gel chromatography (ethyl acetate / hexane 6: 4) afforded 14 mg (54%) of 3- (1H-benzimidazol-2-yl) -6- (3-methoxy-4-methoxymethoxyphenyl) -ΙΗ-indazole as a solid, R _f sm 0.39, p 0.24 (ethyl acetate-hexane 6: 4), ^X H NMR (CDCl3) δ 8.69 (d, H, f = 8 Hz), 7.70 (br s, 2H) 7.58 (s, 1H), 7.53 (d, 1H, J = 8Hz), 7.30-7.15 (m, 7H), 5.30 (s, 2H), 3.97 ( s, 3H), 3.58 (s, 3H), MS (ES) [M + H] / z calc 401, measured 401, [MH] / z calc 399, measured 399.

Example 4 (a)

N- [3- (3-styryl-lH-indazol-6-yloxy) -phenyl] -benzamide

A solution of 0.09 g (0.17 mmol) of N- [3- (2-benzoyl-3-styryl-1H-indazol-6-yloxy) -phenyl] -benzamide in 2 mL of 6N aqueous HCl and 3 mL

The MeOH was heated at 65 ° C for about 4 hours. The cooled solution was poured carefully into a saturated sodium bicarbonate solution. The precipitate was filtered, collected and chromatographed on silica gel eluting with hexane / EtOAc (1: 1). To afford 32 mg (50%) of N- [3- (3-styryl-indazole-6-yloxy) fenylJbenzamidu as a beige solid: ^{Χ Η} NMR (DMSO-d ₆₎ δ 13.50 (s, 1H), 10 32 (s, 1H), 8.23 (d, 1H, J = 8.7Hz), 7.92 (d, 2H, J = 6.8Hz), 7.72 (d, 2H, J = 7.3 Hz), 7.71-751 (m, 7H), 7.51-7.47 (m, 3H), 7.30 (t, 1H, J = 7.2 Hz), 7.05 ( s, 1H), 7.01 (d, 1H, J = 8.7 Hz), 6.86 (dd, 1H, J = 8.2,

2.3 Hz). Anal, calcd for C28H21N3O2 · 0.3 H ₂ O: C, 76, 97, H,

4.98: N, 9.62. Found: C, 76.94, H, 5.13, N, 9.40.

The starting material was prepared as follows:

(I)

acetone reflux. ---- ►

suspension

10.47 g (38.3 mmol) of 3- (benzhydrylidenamino) phenol,

5.00 g (38.3 mmol)

3-Chlorocyclohex-2-enone a

5.82 g (42.1 mmol) of potassium carbonate in 150 ml of acetone was heated at reflux overnight. The cooled reaction mixture was filtered and concentrated under reduced pressure.

The residue was chromatographed on silica gel eluting with hexane / EtOAc (2: 1).

In this way it was obtained

8, 82 (63

%) amino) phenoxy] cyclohex-2-enone as yellow

3- [3- (benzhydrylidene solid): ¹ H

NMR (CDCl 3) δ 7.78 (d, 2H, J = 7.0 Hz), 7.50 (d, 1H, J = 7.1 Hz),

7.45 (d, 2H, J = 7.7 HŽ), 734-7.10 (m 2) 6H), 6, 69 (D, 1H, J ^; 8.0 Hz), 6, 61 (D, 1H, J = 8.0 Hz), 6.38 (with, 1H), 4 89 (with, 1H) 2.55 (t, 2H, J = 6, 2 Hz), 2.34 (t, 2 H, J = 6.2 Hz ) 2.06 (m

2Η). Anal, calcd for C25H21NO2 · 0.2 H ₂ O: C, 80 92; H, 5.81; N,

N, 3.72. Found: C, 81.12; H, 5.81;

3- (benzhydrylidenamino) phenol was prepared as follows: a stirred solution of 15.0 g (82.8 mmol) of benzophenoneimine and 9.03 g (82.8 mmol) of 3-aminophenol in 25 ml of toluene was heated to reflux with removal . H ₂ 0 Dean-Stark trap for 3.5 hours. The crystals formed from the cooled reaction mixture were collected by vacuum filtration, washed with hexane, and air dried. In this way, 17.3 g (76%) of 3- (benzhydrylidenamino) phenol was obtained as a light yellow solid: ¹ H NMR (CDCl 3) δ 7.64 (d, 2H, J = 7.1 Hz), 7.38 (d, 1H, J = 7.1

Hz), 7.34-7.15 (m, 7H), 7.04 (d, 2H, J = 7.2 Hz), 6.88 (t, 1H, J = 8.1 Hz), 6, 82 (d, 1H, J = 8.2 Hz), 6.23 (s, 1H), 6.21 (d, 1H, J = 7.8 Hz). Anal. Calcd for C 19 H 15 NO: C, 83.49, H, 5.53, N, 5.12. Found: C, 83.51, H, 5.65, N, 5.03.

(Ii)

1) UHMDS, -7TC

2) Cinnamoyte chloride

A solution of 3.37 g (11.89 mmol) of 3- [3- (benzhydrylidenamino) phenoxy] cyclohex-2-enone in 20 mL of THF was added slowly to 25.0 mL of a solution of LiHMDS (1.0 M solution in THF) in 10 mL. mL THF at -78 ° C. Five minutes after the addition was complete, 1.98 g (11.89 mmol) of trans-cinnamoyl chloride was added in one portion and stirring was continued at -78 ° C for 30 minutes. The reaction was quenched with saturated NH ₄ Cl solution and extracted with EtOAc (2x). The combined organic layers were washed with saturated NaCl, dried (MgSO 4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane / EtOAc (5: 1) to give 3.34 g (56%) of 3- [3- (benzhydrylidenamino) phenol) -6- (3-phenylacryloyl) cyclohex-2enone as a yellow-orange solid: ¹ H NMR (CDCl ₃ ) δ 15.69 (s,

1H), 7.80 (d, 2H, J = 7.1Hz), 7

1H, J = 15.6 Hz), 6.75 (d, 1H, 8.0 Hz), 6.46 (s, 1H), 4.92 (s, 2.62 (t, 2H, J = 7) , 2 Hz).

H, 5.47, N, 2.82. Found: C, 63-7.01 (m, 15H), 6.93 (d,

J = 7.6 Hz), 6.66 (d, 1H, J =

1H), 2.85 (t, 2H, J = 7.2 Hz), calcd for C34H27NO3: C, 82.07,

H, 5.53; N, 2.81.

(Iii)

IWfcO.HOAe.

BOH.78C —-—— ► Cr • ^ ^{0 solution}

1.81 g (3.64 mmol)

3- [3 (benzhydrylidenamino) phenol] -6- (3-phenylacryloyl) cyclohex-2enone dissolved in 10 mL of HOAc / EtOH (1: 1) was added 2.0 mL (41.23 mmol) of hydrazine hydrate. The solution was heated at 75 ° C for 25 minutes. After cooling, the reaction mixture was carefully poured into saturated sodium bicarbonate solution and extracted with EtOAc (2 x). The combined organic layers were washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane / EtOAc (1: 1). 539 mg (45%) of 3- (3-styryl-4,5-dihydro-1H-indazol-6-yloxy) -phenylamine were obtained as a yellow solid. ¹ H NMR (DMSO-d 6) δ 7.55 (d, 2H, J = 7.2 Hz), 7.38 (t, 2H, J = 7.2 Hz), 7.27 (t, 1H, J = 7.2 Hz), 7.05 (m, 3H), 6.38 (d, 1H, J = 8.0)

Hz), 6.31 (s, 1H), 6.23 (d, 1H, J = 7.9 Hz), 5.52 (s, 1H),

5.26 (s, 2H), 2.92 (t, 2H, J = 8.0 Hz), 2.58 (t, 2H, J = 8.1

Hz). Anal Calculated for C21H19N3O · 0.3 H ₂ O: C, 75 33; H, 5.90; N,

12.55. Found: C, 75.46, H, 5.96, N, 12.35.

(Iv)

To a stirred solution of 50 mg (0.15 nimol)

3- (3-styryl-4,5-dihydro-1H-indazol-6-yloxy) -phenylamine and 54 μΐ (0.31 mmol)

Of Ν, Ν-diisopropylethylamine in 5 ml of CH ₂ Cl ₂ was added 36 μΐ (0.31 mmol) of benzoyl chloride. After 15 minutes, the reaction mixture was diluted with CH ₂ Cl ₂ and washed sequentially with 0.5 N HCl, saturated sodium bicarbonate solution and brine, dried (MgSO ₄ ) and concentrated under reduced pressure. To a stirred solution of the residue in 1,4-dioxane was added 35 mg (0.15 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). After 1 h, the reaction mixture was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with hexane / EtOAc (2: 1). 90 mg (quantitative) of N- [3- (2-benzoyl-3-styryl-1H-indazol-6-yloxy) phenyl] benzamide were obtained as a rust colored solid: ¹ H NMR (CDCl ₃ ) δ 8, 13 (s,

1H), 8.02 (d, 2H, J = 7.0 Hz), 7.94 (d, 1H, J = 8.7 Hz), 7.74 (d, 2H, J = 6.8 Hz) 7.57-7.19 (m, 17H), 6.84 (d, 1H, J = 8.3)

Hz).

N - [3- (3-styryl-1H-indazol-6-yloxy) phenyl] acetamide

Example 4 (b)

The compound of Example 4 (b) was prepared in a similar manner to that described in Example 4 (a) above except that acetic anhydride was used in place of benzoyl chloride in step (iv). ¹ H NMR (DMSO-d 6) δ 13.08 (bs, 1H), 10.03 (s, 1H), 8.22 (d, 1H, J = 8.7 Hz), 7.72 (d, 2H, J =

7.3 Hz), 7.52 (s, 2H), 7.44-7.27 (m, 6H), 7.01 (s, 1H), 6.96 (dd, 1H, J = 8.7) , 2.1 Hz), 6.78 (d, 1H, J = 6.9 Hz), 2.01 (s, 3H). Anal, Calcd for C 23 H ₁₉ N ₃ O ₂ · 0.25 H ₂ O: C, 73, 88, H, 5.26, N, 11.24.Namer: C, 74.20, H, 5.57, N, 10.82 .

Example 5 5-Methyl-thiazole-2-carboxylic acid {3- (3-styryl-1H-indazol-6-yloxy) -phenyl} -amide

A suspension of 5-methylthiazole-2-carboxylic acid {3- [1- (5-methyl-thiazole-2-carbonyl) -3-styryl-1H-indazol-6-yloxyl-phenyl} -amide and 57 mg (0.10 mmol) of 36 mmol) of potassium carbonate in MeOH was stirred at 23 ° C for 20 minutes. The solution was filtered, diluted with EtOAc and washed with brine (x2). The organic layer was dried (MgSO ₄ ) and concentrated under reduced pressure. There was thus obtained 5-methylthiazole-2-carboxylic acid {3- (3-styryl-1H-indazol-6-yloxy) -phenyl] -amide as a tan solid in 47% yield: NMR (DMSO-d6) δ 13.00 (s, 1H ), 10.80 (s, 1H), 8.23 (d, 1H, J = 8.8)

Hz), 7.79 (s, 2H), 7.71 (t, 2H, J = 8.6 Hz), 7.53 (s, 2H),

7.41-7.27 (m, 5H), 7.04 (s, 1H), 7.00 (d, 1H, J = 8.7 Hz),

6.89 (d, 1H, J = 8.5Hz), 2.54 (s, 3H). Anal, calculation for

C ₂₆ H ₂₀ N ₄ O ₂ S 1.15 H ₂ O: C, 65.98, H, 4.75, N, 11.84, S, 6.78. Found: C, 65.99, H, 4.71, N, 11.58, S, 6.76.

The starting material was prepared as follows:

(I)

3- (3-Styryl-4,5-dihydro-1H-indazol-6-yloxy) phenylamine was converted to {3- [1- (5-methylthiazole-2-carbonyl) -3-styryl-1H-indazol-6-yloxylphenyl 5-methylthiazole-2-carboxylic acid amide by treatment with 5-methylthiazole-2-carboxylic acid and HATU (o- (2-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate) in DMF and treatment , DDQ treatment and isolation were analogous to Example 4 (a), step (iv) (50% yield): ¹ H NMR (DMSO-d ₆ ) δ 10.85 (s, 1H), 8.45 (d, 1H) J = 9.8 Hz), 8.24 (m, 3H), 7.99-7.62 (m, 6H), 7.54-7.34 (m, 5H), 6.96 (d, 1H, J = 8.5 Hz), 2.64 (s, 3H), 2.54 (s, 3H).

Example 5 (b)

3-methyl-N- [3- (3-styryl-lH-indazol-6-yloxy) -phenyl] -benzamide

The compound of Example 5 (b) was prepared in a similar manner to that described in Example 5 (a) above except that m-tolyl chloride was used instead of 5-methyl-

thiazole-2-carboxylic acid of and HATU in step) to (i) · ^X H NMR (DMSO-de) δ 13.04 (s, 1H), 10.28 (s, 1H), 8.23 (D, 1H, J = 8.8 Hz), 7.73-7.30 (m, 14 H, 7.05 (s, 1H), 6.99 (D, 1H, J = 8.5

Hz), 6.87 (d, 1H, J = 7.7 Hz), 2.38 (s, 3H). Anal. Calcd for C 29 H 23 N ₃ O ₂ · 0.2 H ₂ O · 0.2 Hexane: C, 77.78, H, 5.66, N, 9.01.Namer: C, 77.80, H, 5.84, N, 8.93.

Example 6 (a)

N- (3- {3- [2- (4-chloro-phenyl) -vinyl] -lH-indazol-6-yloxy} -phenyl) -benzamide

Using N- (3- {1-benzoyl-3- [2- (4-chlorophenyl) vinyl] -1H-indazol-6-yloxyl} phenyl) benzamide, the general procedure of Example 5 (a) was used to prepare the title compound. as an off-white solid in 72% yield: ^lH-NMR (DMSO-d ₆₎ δ 13.07 (s, 1H), 10.32 (s, 1H), 8.24 (d, 1 H, J = 8, 8 Hz), 7.92 (d, 2H, J = 7.1 Hz), 7.76 (d, 2H, J = 8.5 Hz), 7.59-740 (m, 10H), 7.05 (s, 1H), 7.00 (d, 1 H, J = 8.7 Hz), 6.87 (d, 1 H, J =

7.9 Hz). Anal. Calcd for C ₂₈ H ₂₀ ClN ₃ O · 0.4 H ₂ O · 0.15 hexane, C, 71.41, H, 4.75, N, 8.65. Found: C, 71.62; H, 14.83; N, 8.45.

The starting material was prepared as follows:

(i) ο

Using 3- [3- (benzhydrylidenamino) phenoxy] cyclohex-2enone and 3- (4-chlorophenyl) acryloyl chloride (prepared as described below), the general procedure of Example 4 (a), step (ii) was used. The product was used without purification in the hydrazine cyclization, Example 4 (a), step (iii), to give 3- {3- [2- (4-chlorophenyl) vinyl] -4,5-dihydro-1H-indazole-6- Yloxyl} phenylamine as a yellow solid in 30% yield. ¹ H NMR (DMSO-d 6) δ 12.45 (s, 1H), 7.58 (d, 2H, J = 8.5 Hz), 7.43 (d, 2H, J = 8.5 Hz), 5.52 (s, 1H), 5.26 (s, 2H), 2.92 (t, 2H, J = 8.0 Hz), 2.58 (t, 2H, J = 8.0 Hz). Anal, Calc'd for C ₂₁ H ₁₈ ClN ₃ O 1 0.75 H ₂ O: C, 66, 84, H, 5.21, N, 11.1. Namer: C, 66.73, H, 4.89 , N, 11.01.

3- (4-chlorophenyl) acryloyl chloride was prepared as follows: to a stirred suspension of 2.51 g (13.77 mmol) of 4-chloro-cinnamic acid in benzene was added 1.1 ml (15.14 mmol) of thionyl chloride and a catalytic amount of DMAP . The reaction mixture was heated to reflux for 1.5 hours. The volatiles were removed under reduced pressure. The white residue was dissolved in Et ₂ O and concentrated again under reduced pressure to give 2.78 g (quantitative) of 3- (4-chlorophenyl) acryloyl chloride as a white solid: ¹ H NMR (CDCl ₃ ) δ 7.81 (d, 1H, J = 15.6Hz), 7.54 (d, 2H, J = 8.6Hz), 7.44 (d, 2H, J = 8.6Hz), 6.65 (d, 1H, J = 15.6 Hz).

3- {3- [2- (4-Chloro-phenyl) -vinyl] -4,5-dihydro-1H-indazol-6-yloxy} -phenylamine was converted to N- (3- {1-benzoyl-3- [2- (4-chloro-phenyl)] vinyl] -1H-indazol-6-yloxyl} phenyl) benzamide by a procedure

described in the example 4 (a) step (iv) (85% yield). ¹ H NMR (DMSO-de) δ 10.37 (s, 1H), 8.43 (d, 1 H, J = 8.8 Hz), 8, 00 to 7.39 (m, 20H), 7.34 (d, 1 H, J = 8.8 (Hz), 6.93 (D, 1H, J = 8.8 Hz).

Example 6 (b)

N- {3- [3- (2-indolyl) -lH-indazol-6-yloxy] phenyl} -3-methylbenzamide

The compound of Example 6 (b) was prepared similarly

way than has been described in Example 6 (a) above, Besides that, that l-SEM-indazole-2-carboxylic acid the acid was used in step (i) instead of 4-chloro- trans-cinnamic acid. ^J H NMR (DMSO-d 6) δ 13.19 (s, 1H), 11.59 (s, 1 H), 10.29 (s, 1H) 8.23 (d, 1H, J = 8.7 Hz); 73-7.38 (m, 9H), 7.12 (s, 1H), 7.03 (d, 2H, J = 7.3 Hz), 6.88 (d, 1H, J = 7.8) Hz), 2.38 (with, 1H). HRMS [M + H] / z calcd: 459.1821, measured 459.1836.

Example 7

3- (styryl-lH-indazol-6-yloxy) -phenylamine

A suspension of 75 mg (0.23 mmol) of 3- (3-styryl-4,5-dihydro-1H-indazol-6-yloxy) phenylamine and 90 mg of 5% palladium on carbon (Pd / C) was heated at 155 ° C. After 4 hours, 39 mg of 5% Pd / C was added. After 22 hours, 30 mg of 5% Pd / C was added. The reaction mixture was filtered hot after 26 hours. The catalyst was washed and the filtrate concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane / EtOAc (1: 1). The appropriate fractions were concentrated and triturated with CH ₂ C1 ₂ and hexane to give 20 mg (27%) of the title compound as an off-white

solid: ³ Η NMR (DMSO d ₆ ) δ 8.16 (d, 1H, J = 8, 5 Hz), 7.71 (d, 2H, J = 6.7) Hz), 7, 50 (S, 2H), 7.40 (T, 2H, J = 7.0 Hz), 7.30 (d, 1 H, J = 6.5 HZ), 7, 06-6,92 (m, 3H), 6.35 (d, 1 H, J =

8.3 Hz), 6.23 (s, 2H), 5.26 (s, 2H). Anal, calcd for C ₂ H ₁₇ N ₃ O • 0.15 CH ₂ C1 _2: C, 74 69; H, 5.13; N, 12.36. Found: C, 74.64; H, 5.23; N, 12.25.

Example 8 (a)

3- (E-styryl) -6-phenoxy-lH-indazole

A suspension of 200 mg (0.64 mmol) of 3- (E-styryl) -6-phenoxy-4,5-dihydro-1H-indazole and 200 mg of 5% Pd / C in 10 mL of tetralin was heated at 155 ° C for 18 hours . The catalyst was removed by filtration of the hot solution and washed with TFA, EtOAc and MeOH. The filtrate was concentrated under reduced pressure and the residue was chromatographed on silica gel eluting with hexane / EtOAc (2: 1) to give 110 mg (55%) of 3- (E-styryl) -6-phenoxy-1H-indazole as an off-white solid . ^X H NMR

(DMSO-d 6) δ 6, 96 (with , 2H), 7.10 (d, 2H) J = 7.7 Hz), 7.20 (T, 1H, J = 7.1 Hz), 7 30 (t, 1H, J = 7.1 Hz), 7.44 (M, 6H), 7.71 (D, 2H, J = 7.5 Hz) , 8.20 (D, 1 H, J = 9.2 Hž), 12.90 (with, 1H).

Anal. Calc'd for C ₂₁ H ₁₆ N ₂ O · 0.1 H ₂ O: C, 80.28, H, 5.20, N,

N, 8.93. Found: C, 80.20; H, 5.21;

The starting material was prepared as follows:

(i) To a stirred solution of 3-chlorocyclohex-2enone (3.00 g, 23.0 mmol) and phenol (2.16 g, 23.0 mmol) in acetone (25 mL) was added

3.81 g (27.6 mmol) of anhydrous K ₂ CO ₃ powder. After refluxing for 18 hours, the mixture was cooled and filtered. The filtrate was concentrated under reduced pressure and subjected to silica gel chromatography eluting with mixtures

hexane and EtOAc (4: 1) to give 3- fenoxycyklohex-2-enone than white solid compound: ^X 1 HNMR (CDCl ₃₎ δ 2,10 (quintet, 2H, J = 6.3 Hz), 2.40 (t, 2H, J = 6.2Hz) 2.68 (t, 2 H, J = 6.3 Hz), 5.14 (s, 1H), 7.05 (d, 2H, J = 7.5) Hz), 7.26 (t, 1 H, J = 7.3 Hz), 7.41 (T, 2H, J = 7.6Hz).

(ii) A solution of 301 mg (1.6 mmol) of 3-phenoxycyclohex-2-enone in 1 mL

THF was added to a stirred solution of a 1.0 M solution of lithium bis (trimethylsilyl) amide in 3.2 mL of THF at -78 ° C. After 15 minutes, 266 mg (1.6 mmol) of cinnamoyl chloride was added in one portion. After 15 minutes, the reaction mixture was poured into 0.5 N HCl and extracted with EtOAc (2x). The combined organic layers were washed with saturated NaCl solution, dried (MgSO 4 filtered and concentrated under reduced pressure. Chromatography of the residue with hexane-ethyl acetate 4: 1 as eluent afforded 220 mg (43%) of 3-phenoxy-6- (3-phenylacryloyl) cyclohexane. 2-enone as a yellow solid: ^{Χ Η} NMR (CDC1 ₃₎ δ (enol form) 2.66 (t, 2H, J = 7.2 Hz), 2.84 (t, 2H, J = 7.1 Hz ), 5.11 (s, 1H), 6.86 (d, 1H, J = 15.6 Hz), 7.02 (d, 2H, J = 8.1 Hz), 7.20 (m, 2H), 7.28-7.38 (m, 3H) HRMS M + H ⁺ calc 319, 1334, found

319.1340.

(iii) To a stirred solution of 1.13 g (3.55 mmol) of 3-phenoxy-6- (3-phenylacryloyl) cyclohex-2-enone in 20 mL of HOAc / EtOH (1: 1) was added 0.21 mL (4 , 3 mmol) of hydrazine monohydrate. The reaction was heated at 70 ° C for 3 hours, cooled and poured carefully into saturated NaHCO ₃ solution and extracted with EtOAc (2 x). The combined organic layers were washed with saturated NaCl solution, dried (MgSO 4 and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane / EtOAc (2: 1) to give 406 mg (36%) of 6-phenoxy-3-styryl-4. 5-dihydro-1H-indazole (3) as an off-white solid: NMR (DMSO-d 6) δ 2.64 (t, 2H, J = 8.0 Hz), 2.95 (t,

2H, J = 8, 0 Hz), 5, 46 (with, 1H), 7.04 (AB, 2H, J = 16.8 Hz), 7, 15 (D, 2H, J = 8.1 Hz) , 7, 25 (m, 2H); 7.42 (m, 4H) , 7.55 (d, 2H, J = 7.7 Hz), 12 , 44 (with, 1H). Anal, calculation for C2Hi ₈ N ₂ O · 0.2 H ₂ O: c. 79,32, H, 5, 83 , N, 8.81. C 79.36, H,

5.85, N, 8.84.

Example 8 (b)

3- (E-styryl) -6- [4- (methoxymethoxy) phenoxy] -lH-indazole

The compound of Example 8 (b) was prepared in a similar manner to that described in Example 8 (a) above, except that 4- (methoxymethoxy) phenol was used instead of phenol in step (i). ^Δ NMR (DMSO-d ₆ ) δ 12.90 (s, 1H), 8.17 (d, 1H, J = 8.8 Hz), 7.71 (d, 2H, J = 7 _r 6 Hz) 7.50 (s, 3H), 7.41 (t, 2H, J = 7.6 Hz), 7.31 (d, 1H, J = 7.4 Hz), 7.10 (s, 3H) 6.95 (dd, 1H, J = 8.8, 1.9 Hz), 6.84 (s, 1H), 5.20 (s, 2H), 3.42 (s, 3H). 2 \ nal. Calcd for C ₂₃ H ₂₀ N ₂ O ₃ : C, 74.17, H, 5.41,

N, 7.52.Namer: C, 74.21, H, 5.59, N, 7.46.

Example 8 (c)

3- (E-styryl) -6-phenylsulfanyl-lH-indazole

The compound of Example 8 (in a manner as described in, except that thiophenol was used in the example of the ^{phenol.; H} NMR (DMSO-de) δ 7.29 (d, 1 H, prepared in (a) above in (i ) in place of (m, 9H), 7.67 (s, 2H), 7.86 (d, 2H, J = 7.2 Hz), 8.35 (d, 1H, J = 8.5 Hz), 13 , 30 (s, 1H). Anal, calcd for C ₂ H ₁₆ N ₂ s · 0.25 H ₂ O: C, 75.76, H,. 5.00; N, 8.41, s, 9, 63. Found: C, 75.79,

H, 4.99; N, 8.16; S, 9.63.

Example 8 (d)

6- (3-bromo-phenoxy) -3-styryl-lH-indazole

The compound of Example 8 (d) was prepared in an analogous manner to that described in Example 8 (a) above,

except that 3-bromophenol he was used in step (i) instead phenol. ¹ H NMR (DMSO-d 6) δ 13 , 08 (s, 1H) , 23 (d , 1H, J = 8.8 Hz), 7.72 (d, 2H, J = 7.3) Hz), 7.53 (s, 2H), 7.43-7.35 (m, 4H), 7.30 (t, 2H, J = 7.2Hz) ), 7 11 (d, 1 H) , J = 7.2 Hz), 7.09 (s, 1 H), 6.98 (d, IH, J) - 8, 8 Hz). Anal. calculation for C2iHi ₅ BrN2O: C, 64.46, H, 3.86; , Br, 20, 42, N 7.16. Measured: C,

64.31, H, 3.99, Br, 20.52, N, 7.11.

Example 9 (a)

3- (E-styryl) -6- [3-hydroxyphenoxy] -lH-indazole

To a stirred solution of 50 mg (0.13 mmol) of 3- (E-styryl) -6- [3 (methoxymethoxy) phenoxy] -ΙΗ-indazole in 5 mL of CH ₂ Cl ₂ at -25 ° C was added 75 μΐ (0 (57 mmol) of trimethylsilyl bromide. After 1.5 hours, saturated NaHCO ₃ solution was added and the product was extracted with EtOAc (2 x). The combined organic layers were washed with saturated NaCl solution, dried (MgSO ₄ ) and concentrated under reduced pressure. The residue was chromatographed on silica gel eluting with hexane / EtOAc (1: 1) to give after trituration of mixtures of CH ₂ Cl ₂ and hexane 22 mg (50%) of 3- (E-styryl) -6- [3-hydroxy-phenoxy] -ΙΗ- Indazole as an off-white solid: ¹ H

NMR From ₆ ) δ 6.37 (S, 1H); 6.43 (d, 1H); 1H, J = 8.1 Hz) , 6.50 (d, 1 H, J = 8.1 Hz), 6.88 (d, 1 H, J = 8.8 Hz) , 6.92 (with (1H), 7.12 (t, 1H, J = 8.1 Hz), 7.24 (t, 1 H, J = = 7, 3 Hz), 7 31 (t, 2H, J = 7.6: Hz), 7.44 (s, 2H), 7.64 (d, 2H, J = 7.5 Hz) , θ, 12 (d, 1 H, J = = 8.7 Hz) 9.54 (s, 1H). 12 92 (s, 11 H). Anal. computing for C ₂ H 16 N ₂ O ₂ • 0.3 H ₂ O: C, 75. 57. H, 5.01. N, 8.39. measured : C, 75, 74, H 5.11, N, 8.25.

The starting material, 3- (E-styryl) -6- [3- (methoxymethoxy) phenoxy] ΙΗ -indazole, was prepared as described in Example (b).

¹ H NMR (CDCl ₃ ) δ 3 42 (s, 3H), 5.10 (s, 2H), 6.64 (d, 1H , J = 8.2 Hz), 6.72 (with, 1H), 6, 80 (d, 1H, J = 8.3 Hz), 6.98 (with, 1H), 7.00 (d, 1 H, J = 8, 8 Hz), 7.19-7.38 (m, 5H), 7.53 (M, 3H), 7.92 (d, 1 H, J = 8.9 Hz). Anal, calculation for C ₂₃ H ₂₀ N ₂ O ₃ : M + H ⁺ : 373.1552, measured 73,: 1546

Example 9 (b)

3- (E-styryl) -6- [4-hydroxyphenoxy] -lH-indazole

The compound of Example 9 (b) was prepared as in Example (a) above except that 3- (E-styryl) -6- [4- (methoxymethoxy) phenoxy] -1H-indazole was used with styryl) -6- [3- (methoxymethoxy) phenoxy] -lH-indazole.

instead of 3- (E ^X H

NMR

_(DMSO-d6) δ 12 95 (with, 1H), 9.58 (s, 1H), 8.33 (d, 1H , J Hz), 7.89 (D, 2H, J = 7.1 Hz), 7.68 (s, 1H), 7.58 (T, , 1H 7.3 Hz), 7, 48 (D, 1H, J = 7.3 Hz), 7.24 (s, 1H), 7 13 (M, 6.99 (d, 2H, J = 8.8 Hz). HRMS [M + H] / z calcd 329.

9.0

3H),

Readings:

1290

329.1293. Anal, calculation for, J

C ₂ iHi ₆ N ₂ O ₂ · 0,35H ₂ O: C,

75, 36, H

5.03, N, 8.37. Found: C, 75.35, H, 5.22, N, 8.24.

Example 10

6- (1-phenylvinyl) -3-styryl-1H-indazole

16.2 mg ((0.0358 mmol) of 6- (1-phenylvinyl) -3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole was dissolved in 0.6 ml of THF and treated with 0, 6 mL of 1 M tetrabutylammonium fluoride (TBAF) in THF was heated at 60 ° C under an argon atmosphere for 4 hours, cooled, neutralized with excess saturated sodium bicarbonate and the organic extracted with ethyl acetate and concentrated This mixture of 3 compounds (TLC visualization) The reaction mixture was treated with 4 mL of THF / water (1: 1: 2) for 30 min, diluted with 20 mL of toluene, concentrated, neutralized with excess saturated sodium bicarbonate and the organic extracted with ethyl acetate. Purification by silica gel chromatography (ethyl acetate / hexane 2: 8) gave 4.6 mg (40%) of 6- (1-phenylvinyl) -3-styryl-1H-indazole:

R _f sm 0.62, p 0.24 (ethyl acetate: hexane 3: ^7); H NMR (300 MHz, CDC1 ₃₎ δ 7.99 (d, 1 H, J = 8.5 Hz), 7, 60-7.25 (m, 14H);

5.58 (d, 1H, J = 1.1 Hz), 5.56 (d, 1H, J = 1.1 Hz), HRMS (FAB) [M + H] / z calcd 323.1548, measured 323 , 1545th

The starting material was prepared as follows:

(i) ôy number, jay

6-iodoindazole was converted to 3,6-dijódindazol (82%) as described in Example 1 (a), step (v): ^X H NMR (300 MHz, CDCl3) δ 10.3 (br s, 1H). 7.90 (s, 1H), 7.52 (dd, 1H, J = 1.2,

8.5 Hz), 7.24 (d, 1H, J = 8.5 Hz).

SEMBr.TBABr / -Cr

755 mg (2.04 mmol) of 3,6-diiodoindazole was added to 2.5 g of 50% KOH in 2.5 mL of water at 0 ° C and 4 mL of dichloromethane was added. To this mixture was added 6.6 mg (0.02 mmol, 0.01 eq) tetrabutylammonium bromide (TBABr) and 397 μΐ (2.24 mmol, 1.10 eq) of 2- (trimethylsilanyl) ethoxymethyl chloride was added dropwise. (SEM-C1) for 3 minutes. The mixture was stirred rapidly at 0 ° C for 1.5 hours. 20 ml of water and 20 ml of dichloromethane were added and the organic material was separated, dried over sodium sulfate and concentrated. Silica gel chromatography (5% ethyl acetate in hexane, 150 mL silica gel) gave 2 isomeric compounds (1-SEM, 763 mg, 75% and 2-SEM,

105 mg, 10%): R f m 0.08, p 0.34 and 0.27 (1: 9 ethyl acetate / hexane), ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.0 (s, 1H) , 7.55 (d,

1H, J = 8.5Hz), 7.24 (d, 1H, J = 8.5Hz), 5.69 (s, 2H), 3.58 (t, 2H, J = 8.2Hz), 0.90 (t, 2H, J = 8.2Hz), -0.1 (s, 9H).

(Iii)

μΐ (0.20 mmol, 2.0 eq.) of 1-bromostyrene was dissolved in 0.75 mL THF, cooled to -78 ° C and treated with 235 μΐ (0.40 mmol, 4.0 eq.). 70M t-BuLi. The mixture was allowed to warm to -42 ° C for 10 minutes and added to 34 mg (0.25 mmol, 2.5 eq) of freshly dried zinc chloride. The resulting solution was allowed to warm to 23 ° C with stirring for 25 minutes. This mixture was added to a mixture of 50 mg (0.10 mmol, 1 eq.) Of pure 3,6-diiodo-1- [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole and Pd (PPh ₃ ) ₄ 5 mg (0). , 004 mmol, 0.04 eq). After 10 minutes, TLC showed that the reaction was complete and quenched with saturated sodium bicarbonate. The organic was extracted with ethyl acetate, dried over sodium sulfate and concentrated under reduced pressure. Silica gel chromatography (ethyl acetate / hexane 5:95) yielded 33.1 mg (70%) of 3-iodo-6- (1-phenylvinyl) -1- [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole: R f sm 0.39, p 0.36 (1: 9 ethyl acetate / hexane), ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.50 (s, 1H), 7.42 (d, 1H, J = 8, 4 Hz), 7.33 (m, 5H), 7.22 (dd, 1H, J =

1.2, 8.4 Hz), 5.68 (s, 2H), 5.59 (d, 1H, J = 1.0 Hz), 5.57 (d,

1H, J = 1.0 Hz), 3.58 (t, 2H, J = 8.2 Hz), 0.88 (t, 2H, J =

8.2 Hz), 0.90 (s, 9H), HRMS (FAB) [M + H] / z calcd 477.0859, found 477.0866.

(Iv)

FBuU, 2nCl _s , THF, Pd (PPh,)

Preparation of 6- (1-phenylvinyl) -3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole: 23 μΐ (0.174 mmol, 2.5 eq) of E-2-bromostyrene was dissolved in 1.0 mL THF and cooled to 78 ° C. 205 μΐ (0.348 mmol, 5.00 eq) of t-BuLi was added and the mixture was warmed to -42 ° C for 7 minutes to give a deep red mixture. The solution was added via cannula to 29 mg (0.209 mmol, 3.00 eq) of freshly dried zinc chloride and the mixture was allowed to warm to 23 ° C with stirring for 20 minutes. This solution was added via cannula to a clean mixture of 33.1 mg (0.0696 mmol, 1.0 eq) of 3-iodo-6- (1-phenylvinyl) -1- [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole and 4 mg (0.0035 mmol, 0.05 eq) of Pd (PPh ₃ ) ₄ at 23 ° C. This solution was left under stirring for 15 minutes and treated with saturated sodium bicarbonate and extracted with ethyl acetate. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography using two columns (5:95 ethyl acetate / hexane, 12 mL silica gel, and 1:99 ethyl acetate / benzene, 12 mL silica gel) gave 16.2 mg (51%) of 6- (1-phenylvinyl) styryl1- -3- [2- (trimethylsilanyl) ethoxymethyl] -lH-indazole: R _f sm 0.38, p

0.29 (ethyl acetate-hexane 1: ^9); H NMR (300 MHz, CDC1 ₃₎ δ

7.98 (d, 1H, J = 8.4 Hz), 7.62-7.22 (m, 14H), 5.71 (s, 2H),

5.57 (s, 2H), 3.60 (t, 2H, J = 8.2 Hz), 0.90 (t, 2H, J = 8.2 Hz), -, 08 (s, 9H), HRMS (FAB) [M + H] / z calc. 453.2362, found 453.2354.

Example 11

N-methyl-N- (3-styryl-lH-indazol-6-yl) benzene-1,3-diamine

To 237 mg (0.5 mmol) of N-methyl-N- {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} benzene-1,3-diamine was added 10, 1 mL (10.1 mmol) of IM TBAF in THF, followed by 0.34 mL (5.04 mmol) of 10 eq) ethylenediamine. The resulting mixture was heated at 70 ° C for 5 hours. The reaction was then quenched with 10 mL saturated NaHCO ₃ and extracted with 3 x 35 mL EtOAc. The combined EtOAc phases were washed with 5 x 20 mL H ₂ O, then 20 mL brine, dried over Na ₂ SO ₄ , decanted and concentrated under reduced pressure to a foam. The crude material was purified by silica gel chromatography (dichloromethane / ethyl acetate 9: 1) to give 120 mg (70% yield) of N-methyl-N- (3-styryl-1H-indazol-6-yl) benzene-1,3-diamine as foam. R f sm 0.73, R f p 0.27 (7: 3 dichloromethane / ethyl acetate), ¹³ C NMR (75 MHz, CDCl ₃ ) Ô 150, 3, 148, 8, 147.5, 147, 5, 143, 9 143 143 137.5

131.1, 130, 3, 129.3, 128, 9, 128.2, 127.9, 126.7, 121.0, 120.5, 117, 0, 116.0, 112, 6, 109, 8, 109, 0, 98, 3, 40.7, LCMS (ESI) [M + H] / z calcd 341, measured 341. Anal, calcd: C, 77.62, H, 5.92, N, 16 , 46th Found: C, 76.16; H, 5.88; N, 15.95.

The starting material was prepared as follows:

(I)

l _2, 3Ν NaOH, dioxane, 23 ° C

..... 'K

6-nitro-1H-indazole was converted to 50.6 g (87%) of 3-iodo-6-nitro-1H-indazole as described in Example 1 (a), step (v): FTIR (KBr) 3376, 3076 , 2964, 2120, 1739, 1626, 1526, 1439, 1294, 1128, 954 cm ^"1; H NMR (300 MHz, CDC1 ₃₎ delta 8.28 (s,

1H), 8.05 (s, 1H), 7.66 (d, 1H, J = 8.13 Hz), 7.45 (dd, 1H, J)

= 8, 33, 1.38 Hz), 7.17 (d, 1H, J = 1.01 Hz), 7.14 (s, 1 H), 7.03 (d, 1 H, J) = 8.04 Hz), 6.89 (s, 2H), 3.82 (s, 3H) 2.55 (s, 6H) 2.21 (s, 3H) 1.32 (with, 9H), MS (FAB) [M + H] / z calculated 311, measured 311. Anal. calculation: C, 69, 66, H,

5.85, N, 9.03. Found: C, 69.41, H, 5.98, N, 8.79.

(Ii)

SEMCI.TBAB 50% KOH, CH. CL Oto 23 C

3-Iodo-6-nitro-1H-indazole was converted to 10.2 g (81% yield) of 6-nitro-3-iodo- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole as described in Example 10, step (ii): mp 58 ° C. Anal, Calc .: C, 37.24, H, 4.33, N, 10.02. Found: C, 37.21, H, 4.38, N, 10.00.

(iii) & r '·

PdfPPhj ^ JNNlaCO,

TokMaOH (B: 1), MTC

6-nitro-3-iodo- [2- (trimethyl) 11.0 g (26.1 silanyl) ethoxymethyl] -1H-indazole, 4.64 (31.4 mmol) styrylboronic acid and 1.25 g (1, 08 mmol) of Pd (PPh ₃ ) ₄ under argon were added 192 ml of toluene, 4 ml of MeOH and 32.6 ml (65.3 mmol) of 2N aqueous NaOH, and the resulting heterogeneous mixture was heated to 90 ° C. The reaction was diluted with 150 mL EtOAc and 50 mL water, the phases were separated and the organic phase was extracted with 2 x 50 mL EtOAc The combined organic phases were washed with 50 mL brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. Purified by silica gel chromatography (EtOAc: hexane 1: 9) to give 7.65 g (74%) of 6-nitro-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole as a yellow solid: ¹³ C NMR (75 MHz, CDCl ₃ ) δ 148, 3, 145, 0, 141.3, 138.1,

134.2, 130.5, 129, 9, 129.8, 129, 5, 128.1, 127, 4, 123.2, 119, 8, 117, 8, 108.2, 79, 7, 68, 5, 19.2, 0.1, MS (FAB) [M + Na] / z calcd 418, measured 418. Anal. Calcd: C, 63.77, H, 6.37, N, 10.62. Found: C, 64.04, H, 6.29, N, 10.56.

(Iv)

8.1 g (20.5 mmol) of 6-nitro-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole was dissolved in 75 mL of DMF at 23 ° C under an argon atmosphere. 12.9 g (67.7 mmol) of SnCl 2 was added, followed by 1.7 mL (92.2 mmol) of water and the resulting mixture was heated to 50 ° C. After 4 hours, 45 mL (135 mmol) of 3N NaOH was added followed by 100 mL of EtOAc. The resulting emulsion was hot filtered through celite and the celite bed was washed hot with 3 x 100 mL EtOAc. The filtrate was concentrated under reduced pressure, the residue was dissolved in EtOAc, washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give a solid. The crude material was purified by silica gel chromatography (ethyl acetate / hexane 2: 8 to 7: 3) to give 5.1 g (68% yield) of 3-styryl-

1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-ylamine as a yellow solid. MS (FAB) [M + H] / z calc. 366, measured 366.

(in)

To a mixture of 1.1 g (3 mmol) of 3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-ylamine, 0.9 g (3.6 mmol) of mono-iodobenzene, 0.07 g ( BINAP, 34 mg (0.0375 mmol) of Pd 2 (dba) 3, and 1.37 g (4.2 mmol) of CS 2 CO 3 under argon were added with 6 mL of toluene. The resulting heterogeneous mixture was heated to 80 ° C. After 46 hours, cool the reaction to 23 ° C, dilute with 20 mL ethyl acetate (EtOAc), and filter. 5 mL of water was added, the phases were separated and the organic phase was extracted with 2 x 50 mL of EtOAc. The combined organics were washed with brine, then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel chromatography (eluting with a 9: 1 mixture of hexane and EtOAc) to give 7.65 g (74%) of (3-nitrophenyl) [3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] - 1 H-indazol-6-yl} amine as a yellow solid: TLC (hexane / EtOAc 7: 3) R _f sm 0.16, R f p 0.30 (ethyl acetate / hexane 3: 7), FTIR (KBr) 3391, 3059, 2952, 2894, 1614, 1530, 1483, 1346, 1248, 1076, 836, 734 cm ^-1; H NMR (300 MHz, CDC1 ₃₎ δ 7.86 (s, 1H).

7.83 (s, 1H), 7.65 (dt, 1H, J = 2.21, 5.13 Hz), 7.15-7.41 (m,

5H), 6.93 (dd, 1H, J = 1.87, 8.67 Hz), 5.56 (s, 2H), 3.51 (t,

2H, J = 8.17 Hz), 0.81 (t, 2H, J = 7.96 Hz), -0.15 (s, 9H), ¹³ C NMR (75 MHz, CDCl 3) δ 149.6, 144.8, 143.5, 142.4, 140.9, 137.3,

131.8, 130, 3, 129, 0, 128.2, 126.7, 122, 8, 122, 6, 120, 1, 119, 3,

116, 1, 115, 6, 111.4, 98.5, 77.9, 66.7, 18.0, -1.2, MS (ESI) [M + H] / z calcd 487, found 487. anal. Calc'd: C, 66.64; H, 6.21; N, 11.51. Found: C, 66.91; H, 6.21; N, 11.44.

(Vi)

UHMDS.M ^ SO.

THF, -0¾

To 434 mg (0.89 mmol) of (3-nitrophenyl) - {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} amine in 5 mL of THF cooled to -5 ° C in under argon atmosphere, 0.42 mL (4.5 mmol) of dimethyl sulfate was added, followed by 1.8 mL (1.8 mmol) of LiHMDS (1M in THF). After 20 minutes, the reaction was quenched with 2 mL saturated aqueous NH ₄ Cl, then extracted with 3 x 20 mL EtOAc. The combined organics were washed with 10 mL brine, dried over Na ₂ SO ₄ , decanted and concentrated under reduced pressure. Purification by silica gel chromatography (eluting with hexane / EtOAc 9: 1) gave 367 mg (82%) of methyl- (3-nitrophenyl) - {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1Hindazol-6-yl} amine. as an oil: TLC (hexane / EtOAc 7: 3) Rf _f 0.29, Rf p 0.39 (ethyl acetate: hexane 3: 7), FTI'R (KBr) 2951,

2894 1611 1528 1485, 1348, 1248, 1077 cm ^-1 NMR (300 MHz CDC1 ₃ ) δ 7.99 (D, 1H, J = 8.67 Hz) 7.77 (t, 1H, J = 2.25 Hz), 7, 72 (dd, 1 H, J = - 0,79, 2.09 Hz) 7.60 (d, 2H, J = 7.22 Hz), 7.26 -7.54 (m, 7 H) , 7.19 (dd, 1H, J = 0.78, 2 , 41 Hz) 7.07 (Dd, 1H, J = 1.85, 8 69 Hz), 5.70 (s, 2H); 3.63 (T, 2H, J = 8.10 Hz), 3.48 (s, 3H) , 0.92 (t, 2H, J = 8.10Hz) ), - -0.04 (with, 9H), ¹³ C NMR (75 MHz, CDC1 ₃ ) δ 150, 2, 149, 6, 147 1. 143. 5, 1- 42.5.

137.3, 131, 9, 129, 8, 129, 0, 128.2, 126, 8, 123, 1, 122, 6, 120.2,

120.0, 119.7, 114.4, 111.4, 104.5, 78, 0, 66, 8, 41, 1, 18.0,

-1.2, LCMS (ESI) [M + H] / z calcd 501, found 510.

(Vii)

Methyl- (3-nitrophenyl) - {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl] amine was converted to N-methyl N- {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6yl} benzene-1,3-diamine as described in Example 11, step (iv). R f sm 0.55, R _f p 0.31 (ethyl acetate: hexane 3: 7); FTIR (thin film) 3455, 3360, 2951, 2893, 1621, 1601, 1494, 1449, 1249, 1074 cm ^-1, NMR (300 MHz, CDCl ₃ ) δ 7.81 (d, 1H, J = 8.8 Hz), 7.58 (d, 2H, J = 7.21 Hz), 7.26-7, 50 (m 5H), 7.12 (t, 1H, J = 7.93 Hz), 7.01 (d, 1H, J = 1.73 Hz), 6.95 (dd, 1H,

J = 1.99, 8.85 Hz: ), 5.67 (s, 2H) , 3, 63 (t, 2H, J = 8) 12 Hz), 3, 38 (s, 3H) 0.93 (t, 2H, J = 8) 13 Hz), -0.04 (s, 9H); ¹³ C NMR (75 MHz, CDCl ₃ ) δ 150, 3, 149, 0 147.7, 143.4, 143.0, 137.6. 131. 3, 130.4, 128, 9, 128.0, 126.7 , 121.2 , 120.6, 117.3, 117.0, 113. 1, 110.1, 109, 3, 97, 5, 77, 8 66, 6, 41.0, 18.0, -1, 2, LCMS

(ESI) [M + H] / z calcd 471, measured 471.

Example 12 (a)

N- {3- [methyl- (3-styryl-lH-indazol-6-yl) amino] phenyl} acetamide

mg (0.041 mmol) of N-methyl-N- {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} benzene-1,3-diamine prepared in Example 11 was suspended in 0.5 mL of CH 2 Cl 2 at 23 ° C under an argon atmosphere. 81 μΐ (1.0 mmol) of pyridine, 94 μΐ (1.0 mmol) of Ac ₂ O and a catalytic amount of DMAP were added. The reaction immediately became homogeneous. After 1 hour TLC analysis (CH ₂ Cl ₂ : EtOAc 4: 1) showed no starting material. The reaction was quenched with 2 mL aqueous saturated NaHCO ₃ , then diluted with 15 mL EtOAc and the organic phases were washed with 3 mL brine, decanted and concentrated under reduced pressure to an oil. The oil was suspended in 2 mL of MeOH and 83 mg (0.6 mmol) of K ₂ CO ₃ was added. The resulting mixture was stirred at 23 ° C under an argon atmosphere. After 1 h, the reaction was diluted with 15 mL EtOAc and the organic phases were washed with 3 mL brine, decanted and concentrated under reduced pressure. The crude material was purified by semi-preparative HPLC to give 8.4 mg (22%) of N- {3- [methyl- (3-styryl-1H-indazol-6-yl) amino] phenyl] acetamide. ^X H NMR (300 MHz, CDC1 ₃₎ δ 7.86 (d, 1H, J = 8.68 Hz);

7.58 (d, 1H, J = 7.17Hz), 7.16-7.45 (m, 7H), 7.15 (d, 1H, J

8.29 Hz), 6.98 (m, 1H), 6.95 (d, 1H, J = 1.92 Hz), 6.8 (dd,

1H, J = 1.16, 8.05 Hz), 3.37 (s, 3H), 2.14 (s, 3H). LCMS (ESI) [M + H] / z calcd 383, found 383. Anal, calcd: C, 75.37,

H, 5.80; N, 14.65. Found: C, 73.53, H, 6.01, N, 13.73.

Example 12 (b)

N- {3- [methyl- (3-styryl-lH-indazol-6-yl) amino] fenylJbenzamid

The compound of Example 12 (b) was prepared in a similar manner to that described in Example 12 (a) above except that benzoyl chloride was used instead of acetic anhydride. LCMS (ESI) [M + H] / z calcd 475, found 475. Anal. Calcd: C (78.36), H (5.44), N (12.60). Found: C (76.57), H (5.50), N (12.12).

Example 12 (c)

{3- [Methyl- (3-styryl-1H-indazol-6-yl) -amino] -phenyl} -carbamic acid benzyl ester

Example 12 (c) was prepared in a similar manner to that described in Example 12 (a) above except that carbobenzyloxy chloride was used in place of acetic anhydride. R f sm 0.30, R f p 0.57 (CH 2 Cl 2: EtOAc 8: 2), LCMS (ESI +) [M + H] / z calcd 475 measured 475, Anal, calcd: C (75, 93), H (5 52), N (11.81), measured, C (75, 60), H (5.96), N (10.75).

Example 12 (d) 5-Methyl-thiazole-2-carboxylic acid [3- [methyl- (3-styryl-1H-indazol-6-yl) -amino] -phenyl] -amide

To a solution of 26 mg (0.075 mmol) of N-methyl-N- (3-styryl-1H-indazol-6-yl) benzene-1,3-diamine prepared in Example 11 and 64 mg (0.45 mmol) of of methyl-thiazole-2-carboxylic acid in 0.375 mL of DMF at 23 ° C under argon was added 171 mg (0.45 mmol) of HATU. After 1 hour, TLC analysis (CH ₂ Cl ₂ : EtOAc 8: 2) showed no starting material. The reaction was quenched with 2 mL of saturated aqueous NaHCO ₃ , then diluted with 15 mL of EtOAc and the organic phases were washed with 3 mL of brine, decanted and concentrated under reduced pressure. The oil was suspended in 2 mL of MeOH and 62 mg (0.45 mmol) of K ₂ CO ₃ was added. The resulting mixture was stirred at 23 ° C under an argon atmosphere. After 1 hour TLC analysis (CH ₂ Cl ₂ : EtOAc 8: 2) showed no starting material. The reaction was diluted with 15 mL EtOAc and the organic phases were washed with 3 mL brine, decanted and concentrated under reduced pressure to a solid. The crude material was purified by silica gel chromatography (eluting with CH ₂ Cl ₂ : EtOAc 85:15) to give 9.9 mg (28%) of the title compound after purification by semi-preparative HPLC. Rf sm 0.25, Rfp 0.39 (hexane / hexane)

EtOAc 8: 2), LCMS (ESI +) [M + H] / z calcd 466, measured 466.

Anal. Calc'd: C (69.65), H (4.98), N (15.04), S (6.89).

Found: C (69.24), H (5.35), N (13.97), S (5.95).

Example 13

N- [3- (3-styryl-1H-indazol-6-ylamino) phenyl] benzamide

N- (3- {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-ylamino} phenyl) benzamide was converted to N- [3- (3styryl-1H-indazol-6-ylamino) ) phenyl] benzamide as described in Example 11. LCMS (ESI) [M + H] / z calcd 431, measured 431. Anal, calcd: C, 78.12, H, 5.15, N, 13.01 . Found: C, 77.06; H, 6.91; N, 9.88.

The starting material was prepared as follows:

(I)

(3-Nitrophenyl) - {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} amine, prepared in Example 11, step (vi), was converted to N- {3- styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} benzene-1,3-diamine as described in Example 11, step (iv). LCMS (ESI) [M + H] / z calcd 457, measured 457.

(Ii)

To a solution of 91 mg (0.2 mmol) of N- {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} benzene-1,3-diamine and 0.081 ml (1, 0 mmol) of pyridine in 0.5 mL of CH 2 Cl 2 cooled to -5 ° C under an argon atmosphere was added 0.028 mL (0.24 mmol) of benzoyl chloride. After 0.5 h, the reaction was quenched with saturated aqueous NaHCO 3, then extracted with 2 x 5 mL CH ₂ Cl ₂ .

The combined organics were washed with 5 mL of brine, dried over NaCl

Na ₂ SO ₄ , decanted and concentrated under reduced pressure to give an oil.

on silica gel

The crude material was purified by chromatography (eluting with hexane / EtOAc 3: 2) to give

108 mg (96% yield) of N- (3- {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-ylamino} phenyl) benzamide. R f sm 0.35, R _f p 0.44 (ethyl acetate-hexane 1: 1); FTIR (thin film) 3320, 2951, 2893, 1657, 1604, 1537, 1493, 1409, 1303, 1248, 1074 cm ^{- 1} , LCMS (ESI) [M + H] / z calcd 561, found 561.

Anal, Calc .: C, 72.82, H, 6.47, N, 9.99. Found: C, 72.33, H, 6.39, N, 9.81.

Example 14

Methylphenyl (3-styryl-lH-indazol-6-yl) -amine

Methylphenyl- [3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1Hindazol-6-yl} amine was converted to methylphenyl- (3-styryl-1Hindazol-6-yl) amine as described in Example 11. MS (ESI) [M + H] / z calc 326, found 326.

The starting material was prepared as follows:

(I)

1) NaNO ₂ (aq) AcOH, tone. HCl 0 * C

2) Kl / I ₂ (aq) 0-23 ”C

To a solution of 1.58 g (4 mmol) of 3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-ylamine in 14 mL of AcOH, 3 mL of water and 1.67 mL of concentrated HCl cooled to 2 mL. ° C was added 304 mg (4.4 mmol) of a solution of NaNO ₂ in 0.5 mL of water over 5 minutes. The resulting dark red solution was stirred at 2 ° C for 0.5 h, then 797 mg (4.8 mmol) of KI solution and 610 mg (2.4 mmol) of I ₂ in 1 mL of water were added dropwise so that the internal temperature was kept below 5 ° C. After 2 hours at 2 ° C, the reaction was allowed to stir at 23 ° C for 17 hours. Quench the reaction with 3N aqueous NaOH, dilute with 50 mL EtOAc and 15 mL H ₂ O, separate the phases and extract the aqueous phase with 2 x 15 mL EtOAc. The combined organic phases were washed with 3 x 20 mL of 5% NaHSO 3, 15 mL of brine, dried over Na ₂ SO 4, decanted and concentrated under reduced pressure. The crude reaction mixture was purified by silica gel chromatography (eluting with 1: 1 hexanes / EtOAc) to give 1.3 g (68% yield) of 6-iodo-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H- indazole as a white solid. ^Δ NMR (300 MHz, CDCl ₃ ) δ 8.03 (s, 1H), 7.79 (d, 1H, J = 9.0 Hz), 7.30-7, 60 (m, 8H), δ 73 (s, 2H), 3.63 (t, 2H, J = 6.0 Hz), 0.96 (t, 2H, J = 6.0 Hz), 0.0 (s, 9), ¹³ C NMR (75 MHz, CDCl 3) δ 143.6, 142.4, 137.2, 132.1, 130.8, 129, 0, 128, 3,

126, 8, 122.5, 122.4, 119, 6, 119, 5, 92.9, 78.1, 66, 9, 18, 0, 1.2. Anal, Calcd: C, 52.94, H, 5.29, N, 5.88. Measured: C,

52, 66, H, 5.29, N, 5.74.

(Ϋ)

6-Iodo-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole was converted to methylphenyl- {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl } amine as described in Example 11, step (v). R _f 0.35 R _f 0.13 (EtOAc: hexane 1: 9), IR (KBr) 3031, 2951, 1625, 1595, 1498, 1449, 1326, 1303, 1248, 1212, 1076, 835, 694 cm ^-1 , MS (ESI) [M + H] / z calcd 456, measured 456.

Example 15

N- [3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -lH-indazol-6-yl] -N-methyl-benzene-1,3-diamine

[3- (2-Benzo [1,3] dioxol-5-ylvinyl) -1H-indazol-6-yl] methyl (3-nitrophenyl) amine was converted to N- [3- (2-benzo [1,3] 1-dioxol-5-ylvinyl) -1H-indazol-6-yl] -N-methylbenzene-1,3-diamine as described in Example 11, step (iv). LCMS (ESI) [M + H] / z calcd 385, found 385. Anal, calcd: C, 71.86, H, 5.24, N, 14.57. Found: C, 70, 99, H, 5 60, N, 13.80.

The starting material was prepared as follows:

(I)

MfPPhj ^ žNNajCO,

Dioxin »Sun, 90 ° C

To a mixture of 4.2 g (10 mmol) of 6-nitro-3-iodo- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole, 3.46 g (15 mmol) of boronic acid and 0.58 g (0.5 mmol) Pd (PPh ₃ ) ₄ at 23 ° C under argon was added 38 mL 1,4-dioxane and 12.5 mL (25 mmol) 2N aqueous NaOH. The resulting mixture was heated to 90 ° C. After 2 hours, dilute the reaction with 100 mL EtOAc and 70 mL water, separate the phases and extract the organic phase with 2 x 100 mL EtOAc. The combined organic phases were washed with 20 ml of brine, and then dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with a 9: 1 mixture of hexane and EtOAc) to give

4.15 g (94% yield) of 3- (2-benzo [1,3] dioxol-5-ylvinyl) -6-nitro- [2- (trimethylsilanyl) ethoxymethyl] -4-indazole as a yellow solid. FTIR 2950, 2898, 1523, 1501, 1483, 1446,

1344, 1249, 1080, 1043, 927 cm ^-1; H NMR (300 MHz, CDC1 ₃₎ δ 8.56 (dd, 1H, J = 0, 68, 1, 75 Hz), 8.14 (d, 1H, J = 1.78 Hz), 8.13 (d, 1H, J = 0.67 Hz), 7.50 (d, 1H, 16.53 Hz), 7.25 (d, 1H,

16.52 Hz), 7.18 (d, 1H, J = 1.67 Hz), 7.07 (dd, 1H, J = 1.65,

8.13 Hz), 6.88 (d, 1H, J = 8.0 Hz), 6.05 (s, 2H), 5.84 (s,

2H), 3.66 (t, 2H, J = 7.33 Hz), 0.97 (t, 2H, J = 7.24 Hz), 0.0 (s, 9H), ¹³ C NMR (75 MHz) , CDC1 ₃ ) δ 148, 5, 148.2, 147, 0, 143, 9, 140, 1, 132.7, 131.3, 126, 1, 122.3, 121.9, 116.7, 116 , 5, 108.7, 106, 9, 105, 7, 101, 5, 78, 4, 67.2, 17.9, -1.3, LCMS (ESI) [M + H] / z calcd 531, measured 531.

100 (ii)

3- (2-Benzo [1,3] dioxol-5-ylvinyl) -6-nitro-1- [2- (trimethylsilanyl) ethoxymethyl] -4-indazole was converted to 3- (2-benzo [1,3] dioxol- 5-ylvinyl) -1- [2- (trimethylsilanyl) ethoxymethyl] 1H-indazol-6-ylamine as described in Example 11, step

(Iv) . ^J H NMR (300 MHz, CDCl ₃ ) Ô 7.73 (d, 1H, J = 8.56Hz) 7, 52 (D, 1H, J = 16.57 Hz), 7.18 (d, 1H, J) = 16.56 Hz), 7.10 (D, 1H, J = 1.49 Hz), 6.98 (dd, 1 H, J = 1, 52, 8.06 Hz), 6.80 (D, 1H, J = 8.01 Hz), 68 (d, 1H, J = 1.44) Hz), 6.63 (dd, 1 H, J = 1.86 , 8, 57 Hz), 5.95 (s, 2H), 5.59 (s, 2H), 3.59 (t, 2H, J = 8, 17 Hz) , 0.9 1 (t, 2H, J = 8, 33 Hz), 0, O 4 (s, 9H), ¹³ C NMR (75

MHz, CDC1 ₃₎ δ 148, 3, 147, 6, 146, 4, 143, 4, 143, 0, 132, 0, 130, 8, 122.0, 121 7, 118.8, 116.5, 113, 1, 108, 5, 105, 5, 101.3, 92.9,

77, 6, 66, 3, 17.9, -1.3. LCMS (ESI) [M + H] / z calcd 410, measured 410.

(Iii)

3- (2-Benzo [1,3] dioxol-5-ylvinyl) -1- (2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-ylamine was converted to {3- (2-benzo [1,3] Dioxol-5-ylvinyl) -1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} - (3-nitrophenyl) amine as described

101 in Example 11, step (v). ¹³ C

NMR (75 MHz, CDCl ₃ ) δ

150.8.

149.7,

149.1.

146, 0,

144.8.

143.6.

142.1.

133.1,

132.7.

131.6.

124.0.

123.8.

123.1.

120.4.

119.5,

117.2.

116.8.

112.6.

109.9.

106.9.

102.6,

99.7.

79.1.

67.9.

19.2.

0.0.

MS [M + H] / z calc. 531, found 531. Anal.

calculation:

C, 63.38, H,

5.70, N, 10.56.

Found: C, 63.49, H,

5.76, N,

10, 42

{3- (2-Benzo [1,3] dioxol-5-ylvinyl) -1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} - (3-nitrophenyl) amine was converted to {3 - (2-benzo [1,3] dioxol-5-ylvinyl) -1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} methyl- (3-nitrophenyl) amine as described in Example 11, step (vi). FTIR (KBr) 2952, 2894, 1612, 1529, 1503, 1489, 1446,1407,

1348, 1306, 1251, 1077, 1039 cm ^-1 , ¹³ C NMR (75 MHz, CDCl 3) δ

150, 1, 149, 5, 148.4, 147, 8, 147, 0, 143, 5, 142, 4, 131, 8, 131.5, 129, 8, 123, 0, 122.49, 121, 9, 120, 1, 119, 5, 118.2, 114.3, 11.3, 108, 7, 105, 7, 104, 5, 101.4, 78.0, 66, 8, 41, 0, 17.9, -1.2. MS (FAB) [M + H] / z calcd 545, measured 545. Anal. Calcd: C, 63.95, H, 5.92, N, 10.29. Found: C, 62.63; H, 5.72; N, 9.62.

(in)

102

{3- (2-Benzo [1,3] dioxol-5-ylvinyl) -1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl] methyl (3-nitrophenyl) amine was converted to [3- (2-benzo [1,3] dioxol-5-ylvinyl) -1H-indazol-6-yl] methyl- (3-nitrophenyl) amine as described in Example 11. LCMS (ESI) [M + H] / z calcd Anal. Calc .: C, 66.66, H, 4.38, N, 13.52. Found: C, 66.56, H, 4.48, N, 13.35.

Example 16 (a)

N- (3 - {[3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -lH-indazol-6-yl] -methyl-amino} -phenyl) -benzamide

N- [3- (2-benzo [1,3] dioxol-5-ylvinyl) -1H-indazol-6-yl] N-methylbenzene-1,3-diamine (prepared as described in Example 15) was converted to N- (3 - {[3- (2-benzo [1,3] dioxol-5-ylvinyl) -1H-indazol-6-yl] methylamino} phenyl) benzamide as described in Example 12 (a). LCMS (ESI) [M + H] / z calcd 489, found 489. Anal. Calcd: C, 73.76; H, 4.95; N, 11.47. Found: C, 73.19, H, 5.09, N, 11.20.

103

Example 16 (b)

N- (3 - {[3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -lH-indazol-6-yl] methylamino] phenyl) -3-methyl-benzamide

The compound of Example 16 (b) was prepared in a similar manner to that described in Example 16 (a) above, except that m-toluyl chloride was used in place of benzoyl chloride. LCMS (ESI) [M + H] / z calcd 504, measured 504. Anal, calcd: C, 74.09, H, 5.21, N, 11.15. Found: C, 73.04; H, 5.84; N, 10.29.

Example 16 (c)

N- (3 - {[3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -lH-indazol-6-yl] methylamino} phenyl) -3-dimethylamino-benzamide

Example compound

16 (c) was prepared in a similar manner to that described for m-dimethylaminobenzoyl chloride in Example 16 (a) except that it was used instead of benzoyl chloride. LCMS (ESI) [M + H] / z calcd 532, found 532.

104

Anal, Calc .: C, 72.30, H, 5.50, N, 13.17. Measured: C,

H, 5.80; N, 12.75.

Example 16 (d)

N- (3 - {[3- (2-Benzo [1,3] dioxol-5-yl-vinyl) -lH-indazol-6-yl] -methyl-amino} -phenyl) -3-trifluoromethyl-benzamide

The compound of Example 16 (d) was prepared in a similar manner to that described in Example 16 (a) except that m-trifluoromethylbenzoyl chloride was used in place of benzoyl chloride. LCMS (ESI) [M + H] / z calcd 557, measured 557. Anal, calcd: C, 66.90, H, 4.17, N, 10.07. Found: C, 66.64, H, 4.34, N, 9.82.

Example 16 (e)

3-Acetyl-N- (3 - {[3- (2-benzo [1,3] dioxol-5-ylvinyl) -1H-indazol-6-yl] methylamino} phenyl) benzamide

The compound of Example 16 (e) was prepared in a similar manner to that described in Example 16 (a) except that

105 m-acetylbenzoyl chloride was used instead of benzoyl chloride.

LCMS (ESI) [M + H] / z calcd 531, found 531. Anal, calcd: C, 72.44, H, 4.94, N, 1056. Found: C, 55.51, H,

4.21, N, 7.58.

Example 16 (f)

6- [N- (3- (4-tert-butyl-3-hydroxybenzamido) phenyl) -N-methylamino] -3-E - [(3,4-methylenedioxyphenyl) ethenyl] -lH-indazole

compound from Example 16 (f) bola p ripravená like way was described in Example 16 (a) except that that 3-tert-butyl-4 -hydroxybenzoic acid, HATU a TEA were used instead of benzoyl chloride. ^X H NMR (300MHz, CD ₃ OD) δ 7, 90 (d, 1 H, J = 8.91 Hz), 7.83 (d, 1 H, J = 2.29 Hz), 7, 63 (Dd, 1 H, J = 8.36, J = 2.31 Hz), 7.54 (t, 1 H, J = 1, 97 Hz); 7.25 - 7,43 ( m, 4H), 7.14-7.20 (m, 2H) 7.06 (dd , 1H, J = 8.11 Hz, J = 1.55 Hz), 6.96 (dd, 1H, J = = 8.93 Hz, 1 = 1, 97 Hz), 6.90 (m, 1H), 6.82 (t, 2H, J = 8.28 Hz), 6.0 (with, 2H), 3, 41 (s, 3H) 1.42 (s, 9H).

Example 17

Phenyl- (3-styryl-lH-indazol-6-yl) -methanone

TBAF, THF, 67 ° C

NH,

106

Phenyl- {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl] methanone was converted to 30 mg (78%) of phenyl- (3-styryl-1H-indazol-6-yl) methanone as has been described in the example

11. MS (ESI) [M + H] / z calcd 325, measured 325. Anal, calcd: C, 81.46, H, 4.97, N, 8.46. Found: C, 80.36, H,

5.16, N,

8.51.

The starting material was prepared as follows:

To a solution of 143 mg (0.3 mmol) of 6-iodo-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl) -1H-indazole, prepared in Example 14, step (i), in 1 mL of THF, cooled to At -78 ° C under argon, n-BuLi (0.2 mL, 0.315 mmol) was added dropwise. The resulting mixture was stirred at -78 ° C for 30 minutes, then 0.035 mL (0.33 mmol) of a solution of benzaldehyde in 0.5 mL of THF was added via cannula. After 0.5 h, the reaction was quenched with saturated aqueous NH ₄ Cl and diluted with 10 mL EtOAc and 3 mL H 2 O. The phases were separated and the aqueous phase was extracted with 2 x 10 mL EtOAc. The combined EtOAc layers were washed with 5 mL brine, dried over Na ₂ SO ₄ , decanted and concentrated under reduced pressure. The crude mixture was purified by silica gel chromatography (eluting with hexane-EtOAc 4: 1) to give 68 mg (50% yield) of phenyl- {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole-6. -yl} methanol. Rf sm = 0.72, Rf p = 0.39 (7: 3 hexane / EtOAc), FTIR (thin film) 3368, 2952, 2893,

1621, 1478, 1449, 1374, 1307, 1249, 1216, 1078, 960, 859, 835 cm < ^{-1 &gt};. MS (ESI) [M + H] / z calc 457, measured 457.

(Ii)

107

To a solution of 68 mg (0.15 mmol) of phenyl {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl} -1H-indazol-6-yl] methanol in 3 mL of dichloromethane at 23 ° C under argon was added 190 mg (0.45 mmol) of periodate (Dess-Martin reagent). The resulting mixture was stirred at 23 ° C for 1 hour. The solution was then diluted with 3 mL of hexane, then filtered through celite and concentrated under reduced pressure to a solid. The crude mixture was purified by silica gel chromatography (eluting with hexane / EtOAc 9: 1) to give 54 mg (79% yield) of phenyl {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl} -1H-indazole-6- yl} -methanone. Rf sm = 0.41, Rf p = 0.63 (7: 3 hexane / EtOAc), FTIR (thin film) 3059, 2952, 2894, 1659, 1474, 1448, 1307,

1249, 1078, 836, 649 cm ^-1 . MS (ESI) [M + H] / z calc 455, measured 455.

Example 18 (3-Aminophenyl) - (3-styryl-1H-indazol-6-yl) methanone

(3-Aminophenyl) - {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl] -methanone was converted to (3-aminophenyl) - (3-styryl-1H-indazol-6-yl) methanone as It described for Example ^{11; H} NMR (300 MHz, CDC1 ₃₎ δ 8.07 (dd, 1H, J = 0.71, 8.50 Hz);

7.91 (s, 1 H), 7.64 (dd, 1 H, J = 1, 35, 8, 48 Hz), 7.54-7, 60 (m,

108

2Η), 7.46 (d, 2H, J = 12.84 Hz), 7.35-7.40 (m, 2H), 7.22-7.31 (m, 2H), 7.16-7 13 (m, 2H), 6.91 (ddd, 1H, J = 1.08, 7.89 Hz). LCMS (ESI) [M + H] / z calc 340, found 340.

The starting material was prepared as follows:

(I)

6-Iodo-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl) -1H-indazole was converted to (3-nitrophenyl) - {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl) -1H-indazole- 6-yl] methanol as described in Example 17, Step (i). R _f sm = 0.71, R _f p = 0.25 (7: 3 hexane: EtOAc), FTIR (thin film) 3369, 3061, 2952, 2894, 2361, 1620, 1578, 1530, 1478, 1449, 1350, 1308, 1249

1215, 1080, 961, 859 cm ^-1; H NMR (300 MHz, CDC1 ₃₎ δ 8.35 (s, IH), 8.14 (dd, IH, J = 1.34, 8.14 Hz) 7.99 (d, 1H, J = 8.38)

Hz), 7.76 (D, IH, J = 7.72 Hz); 7.68 (s, 1H); 7.59-7.30 (m, 8H), 7.21 (D, IH, J = 8.33 Hz), 6.09 (s, 1H), 5.73 (s, 2H). 3, 61 (T, 2H, J = 8.30 Hz), 0, 90 (t, 2H, J = 8) , 30 Hz), -0.06

(S, 9H). ¹³ C NMR (75 MHz, CDCl ₃ ) δ 148, 5, 145, 9, 143, 4, 142, 4, 141.3, 137, 1, 132.7, 132, 0, 129, 5 ,. 128, 9, 128.2, 126, 7, 122, 6, 122, 6, 121.8, 121.5, 120, 8, 119, 6, 107, 8, 77.7, 75, 4, 66, 8

17.8, -1.3. Anal. Calc'd: C, 67.04; H, 6.23; N, 8.38.

Found: C, 66.93, H, 6.20, N, 8.41.

(Ii)

109

(3-nitrophenyl) - (3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl] methanol was converted to (3-nitrophenyl) - {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] 1 H -indazol-6-yl-methanone, as described in Example 17, step (ii) 129 mg 91%). R _f sm 0.46, R _f p = 0.23 (7: 3 hexane: EtOAc), FTIR (thin film) 3082, 2952, 2894, 1665, 1613, 1532, 1476, 1349, 1298, 1250, 1080, 836, 718 cm ^-1 , LCMS (ESI) [M + H] / z calcd 500, measured 500.

(Iii)

(3-Nitrophenyl) - {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} methanone was converted to (3aminophenyl) - {3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazol-6-yl} methanone as described in Example 11, step (iv) 102 mg (84%). LCMS (ESI) [M + H] / z calc 340, found 340.

Example 19 (a)

N- [3- (3-styryl-1H-indazole-6-carbonyl) phenyl] acetamide

110

The (3-aminophenyl) - (3-styryl-1H-indazol-6-yl) methanone prepared in Example 18 was converted to 12.2 mg (78%) of N- [3- (3-styryl-1H-indazole) 6-carbonyl) phenyl] acetamide as described in Example 12 (a). Rf dew = 0.16, Rf p = 0.35 (8: 2

CH ₂ Cl ₂ : EtOAc), LCMS (ESI) [M + H] / z calcd 382, measured 382. Anal, calcd: C, 75.57, H, 5.02, N, 11.02. Found: C, 74.32; H, 5.41; N, 10.54.

Example 19 (b)

N- [3- (3-styryl-lH-indazole-6-carbonyl) -phenyl] -benzamide

The compound of Example 19 (b) was prepared in a similar manner to that described in Example 19 (a) except that benzoyl chloride was used in place of acetic anhydride. ^H NMR (300 MHz, (CDCl3) δ 8.40 (s, 1H), 8.02 (d, 1H, J = 8.49 Hz), 7.98 (d, 1H, J = 1.01 Hz 7.95 (s, 1H), 7.95 (s, 1H), 7.83-7.88 (m, 3H), 7.65 (dd, 1H, J = 1.04, 8, 48) Hz), 7, 29-7, 56 (m, 11H) MS (ESI) [M + H] / z calcd 444, measured 444. Anal, calcd: C, 78.54, H, 4.77, N Found: C, 78.01, H, 4.87, N, 9.47.

9.32.

Example 19 (c) III

[3- (3-Styryl-1H-indazole-6-carbonyl) -phenyl] -carbamic acid benzyl ester

The title compound was prepared in a similar manner to that described in Example 19 (a) except that carboxybenzyloxy chloride was used instead of acetic anhydride. ^X H NMR (300 MHz, _DMSO-ds) δ 8.37 (d, 1H, J = 8.48 Hz), 7.98 (s,

1H), 7.88 (s, 1H), 7.79 (s, 1H), 7.75 (d, 2H, J = 7.44 Hz), 7, 61 (d, 2H, J = 1.81 Hz), 7.58 (s, 1H), 7.51 (t, 1H, J = 7.79) Hz); 7.42 (t, 5H, J = 6.56 Hz), 7.31-7.37 (m, 4H), 5.16 (s, 2H); LCMS (ESI) [M + H] / z calcd 474, found 474. Anal.

Calc'd: C, 76.09; H, 4.90; N, 8.87. Found: C, 73.82, H,

4.93, N, 8.27.

Example 19 (d) 5-Methylthiazole- [3- (3-styryl-1H-indazole-6-carbonyl) -phenyl] -amide

Of 2-carboxylic acid

5-methylthiazole (3-aminophenyl) - (3-styryl-1H-indazol-6-yl) methanone was converted to 9.9 mg of 28%) [3- (3-styryl-1H-indazole-6-carbonyl) phenyl] amide -2-carboxylic acid as described in Example 12 (d). ^X H NMR (300 MHz, CDCl 3) δ

8.15 (d, 1H, J = 8.49 Hz), 8.09 (t, 1H, J = 1.86 Hz), 8.04

112

(Dd, 1 H, J = 1.0. 7, 98 Hz), 7.99 (with, 1H), 7.75 (dd, IH, J = 1.31. 8.47 Hz) 1.7, 67 (s, 1H), 7, 63 (D, 2H, J = 7.30 Hz), 7.54- 7.58 (m, 3H) 7.50 (with, 1H), 7.42 (T, 3H, J = 8.09 Hz), LCMS (ESI) [M + H] / z calculated 465. measured 465th

Example 19 (e)

6- [3- (5-Methyl-pyridin-3-ylcarboxamido) -benzoyl] -3-E-styryl-1H-indazole

19 (e)

The compound of the example was prepared in a similar manner as in the example

19 (d) except that 5-methylnicotinic acid was used in place of 5-methylthiazole-2-carboxylic acid. ¹ H NMR (300 MHz, CDCl 3) δ 9.22 (s, 1H),

8.99 (d, 1H, J = 0.59 Hz), 8.67 (s, 1H), 8.24 (s, 1H), 8.16 (d, 1H, J = 8.32 Hz), 2.97 (dd, 1H, J = 8.3 Hz, J = 0.94 Hz), 7.72 (d, 1H, J = 16.65 Hz), 7.64 (d, 2H, J = 7) 21 Hz), 7.197.47 (m, 8H), 6.95 (d, 1H, J = 6.43 Hz), 2.49 (s, 3H). MS (ESI +) [M + H] / z calcd 459, measured 459. Anal, calcd: C,

75.97. H, 4.84. N, 12.22. measured

C, 75, 86. H, 4.94. N,

12.10.

6- [3- (Indol-4-ylcarboxamido) benzoyl] -3-E-styryl-1H-indazole

Example 19 (f)

113

Example 19 (f) was prepared in a similar manner to Example 19 (d) except that 1H-indole-4-carboxylic acid was used instead of 5-methylthiazole-2-carboxylic acid. LCMS (ESI +) [M + H] / z calcd 483, found 483. Anal. Calcd: C, 77.16, H, 4.60, N, 11.61. Found: C, 76.15; H, 4.49; N, 11.31.

Example 19 (g)

6- [3- (Pyridin-2-ylacetamido) benzoyl] -3-E-styryl-1H-indazole

Example 19 (g) was prepared in a similar manner to Example 19 (d) except that pyridine-2-acetic acid was used in place of the compound. ^X H NMR (300 MHz, CDC1 ₃₎ δ 8.50 (dd, 1H, J = 4.86 Hz, J = 0.91 Hz), 8.37 (d, 1H, J = 8.51 Hz); 8.09 (s, 1H), 7.94 (d, 1H, J = 7.89 Hz), 7.87 (s, 1H), 7.73-7.79 (m, 3H), 7.25 -7, 60 (m, 10H), 3.86 (s, 2H). MS (ESI) [M + H] / z calc. 459, measured 459. Anal. Calcd: C, 75.97, H, 4.84, N, 12.22. Found: C, 74.70, H, 4.83, N, 11.99.

Example 19 (h)

6- [3- (2-Methylpropionamido) benzoyl] -3-E-styryl-1H-indazole

114

Compound as in Example, instead of acetyl chloride.

(h) has been prepared similar to (a). Isobutyryl chloride was ^{used; H} NMR (300 MHz, DMSO-de) δ 8.38 (d, (t, 1H), 7.96

7.75 (d, 2 H,

7.71 (d, (m, 1H)); 2.60 (m, 1H, J)

6.82 Hz), 1.1 (d, 6H, J = 6.82 Hz). (MS (ESI +) [M + Na] / z calcd 432, measured 432. Anal, Calcd: C,

76.26. H,

5.66. N, 10.26. Found: C, 75.14. H, 5.62. N, 10.08.

Example 19 (i)

6- [3- (2-acetamido-2-phenylacetamido) benzoyl] -3-E-styryl-indazole

The compound of Example 19 (i) was prepared in a similar manner to Example 19 (d) except that acetylamino-2-phenylacetic acid was used in place of 5-methylthiazole-2-carboxylic acid. ¹ H NMR (300 MHz, DMSO-d 6) δ 13.5 (s,

1H), 10, 6 (s, 1 H), 8, 66 (d, 1 H, J = 7.66 Hz 8.36 (d, 1 H, J = 8.47 Hz), 8.07 (s, 1H) , 7.92 (d, 1 H, J = 7.63 Hz), 7.86 (with, 1H), 7.75 (d, 2H) J - 7.33 Hz), 7.29-7.60 (m, 13H, 5.61) (D, 1H, J = 7, 6 Hz), 1 , 92 (s, 3 H). LCMS (ESI) [M + H] / z calcd 515. measured 515. anal . calculation: C, 74, 69. H, 5.09. N, 10, 89th

Found: C, 73.01. H, 5.01. N, 10.60.

115

Example 19 (j)

6- [3- (pyridin-4-ylcarboxamido) benzoyl] -3-E-styryl-lH-indazole

The compound of Example 19 (j) was prepared in a similar manner to Example 19 (d) except that isonicotinic acid was used instead of 5-methylthiazole-2-carboxylic acid. MS (ESI +) [M + Na] / z calcd 467, found 467. Anal. Calcd: C, 75.66, H, 4.54, N, 12.60. Found: C, 74.17, H, 4.62, N, 12.31.

Example 19 (k)

6- [3- (pyridin-2-ylcarboxamido) benzoyl] -3-E-styryl-lH-indazole

19 (k)

The compound of the example was prepared in a similar manner to that of the carboxylic acid was a carboxylic acid. MS

19 (d) in addition, used in place of (ESI +) [M + Na] /, that pyridine-25-methylthiazole-2 calculated 467, measured 467. Anal. Calcd. C, 75.66, H,

454, N, 12.60.

Found: C, 74.17, H, 4.61, N, 12.44.

Example 19 (1)

6- [3- (isoxazol-4-ylcarboxamido) benzoyl] -3-E-styryl-lH-indazole

116

The compound of Example 19 (1) was prepared in a similar manner to Example 19 (d) except that isoxazole-5-carboxylic acid was used in place of 5-methylthiazole-2-carboxylic acid. MS (ESI +) [M + H] / z calcd 435, measured 435. Anal. Calcd: C, 71.88, H, 4.18, N, 12.90.

Found: C, 71.36, H, 4.33, N, 12.47.

Example 19 (m)

6- [3- (6-chloropyridin-2-ylcarboxamido) benzoyl] -3-E-styryl-indazole

Example 19 (m) was prepared in a similar manner to Example 19 (d) except that 6-chloropyridine-2-carboxylic acid was used in place of 5-methylthiazole-2-carboxylic acid. MS (ESI +) [M + Na] / z calcd 501, found 501.

Example 19 (n)

6- [3- (4-chloro-2 -ylkarboxamido ^j) benzoyl] -3-E-styryl-indazole

117

Example 19 (n) was prepared in a similar manner to Example 19 (d) except that 4-chloropyridine-2-carboxylic acid was used in place of 5-methylthiazole-2-carboxylic acid. MS (ESI +) [M + H] / z calcd 479, found 479. Anal. Calcd: C, 70.22, H, 4.00, N, 11.70. Found: C, 70.07, H, 4.09, N, 11.64,

Example 19 (o)

6- [3- (2-chloropyridin-4-ylcarboxamido) benzoyl] -3-E-styryl-indazole

Example 19 (o) was prepared in a similar manner to Example 19 (d) except that 2-chloroisonicotinic acid was used in place of 5-methylthiazole-2-carboxylic acid. MS (ESI +) [M + H] / z calcd 479, found 479.

Example 19 (p)

6- [3- (2-methylamino-2-phenylacetamido) benzoyl] -3-E-styryl-1Hindazole

118

To a solution of 115 mg (0.2 mmol) of 6- [3- (2- (Nt-butoxycarbonyl-N-methylamino) -2-phenylacetamido) benzoyl] -3-E-styryl-1H-indazole in 2 mL of CH 2 Cl 2 cooled to 0 ° C was added 2 mL of TFA. After 40 minutes, the reaction mixture was quenched with saturated aqueous NaHCO ₃ , then extracted with 2 x 10 mL CH 2 Cl 2. The organic layers were washed with brine, dried over Na 2 SO 4, decanted and concentrated. Purification by silica gel chromatography (1:10 methanol / dichloromethane) afforded 38 mg (39%) of 6- (3- (2-methylamino-2-phenylacetamido) benzoyl) -3-E-styryl-1H-indazole.

MS (ESI +) [M + H] / z calcd 487, found 487. Anal. Calcd: C, 76.52, H, 5.39, N, 11.51. Found: C, 74.99; H, 5.76; N, 10.89.

The starting material was prepared as described below:

(i) 6- [3- (2- (N-t-butoxycarbonyl-N-methylamino) -2-phenylacetamido) benzoyl] -3-E-styryl-1H-indazole

6- [3- (2- (N-butoxycarbonyl-N-methylamino) -2-phenylacetamido) benzoyl] -3-E-styryl-1H-indazole was prepared in a similar manner to Example 19 (d) except that ( t-butoxycarbonylmethylamino) phenylacetic acid was used instead

5-methylthiazole-2-carboxylic acid. MS (ESI +) [M + H] / z calc 587, found 587.

119

Example 20 (a)

6- (3-acetamidophenylsulphanyl) -3-styryl-lH-indazole

-------->

6- (3-acetamidophenylsulfanyl) -3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -4-indazole was converted to 6- (3-acetamidophenylsulfanyl) -3-styryl-1H-indazole as described in the example 11 (30 mg, 81%): R f sm 0.65, p 0.35 (10% methanol in dichloromethane), ^{Τ Η} NMR (300 MHz, CDC1 ₃₎ δ 7.81 (d, 1 H, J =

8.5 Hz), 7.59 (bs, 1H), 7.48-7.0 (m, 13H), 1.98 (s, 3H), HRMS (FAB) [M + Na] / z calcd 408.1147, measured 408.1156.

The starting material was prepared as follows:

(I)

To 1.4 eq. 9-BBN 3-phthalamidothiophenol addition compound prepared in situ as described below was added 250 mg (0.5 mmol) of 3,6-diiodo-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole 87 mg (0.2 eq.) Of Pd (dppf) Cl ₂ and 339 mg (1.6 mmol, 3.00 eq.) Of potassium phosphate in 3.0 mL of DMF. The reaction mixture was heated at 90 ° C for 9 hours. The mixture was cooled and partitioned between ethyl acetate and saturated sodium bicarbonate. The organic material was dried over MgSO4

120 sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (ethyl acetate / hexane 2: 8) afforded 159 mg (50%) of 6- (3-phthalamidophenylsulfanyl) -3-iodo-1H-indole as an oil: ¹ H NMR (300 MHz, CDCl 3) δ 7.93 ( m, 2H), 7.79 (m, 2H), 7.62 (s, 1H), 7.5-7.3 (m, 5H), 7.22 (d, 1H), 5.68 (s) (2H), 3.55 (t, 2H, J = 8.2 Hz), 0.87 (t, 2H, J = 8.2 Hz), -, 06 (s, 9H), HRMS (FAB) [ M + Cs] / z calc. 759.9563, found 759.9571.

The boron reagent was prepared as follows: in a 10 ml Schlenk flask, 3-phthalamidothiophenol was dried under high vacuum. A solution of 1.6 mL (1.0 eq.) Of 9-BBN (0.5M in THF) was added. The mixture was heated to 55 ° C for 2 hours. The volatile material was removed under argon at 70 ° C for 1.5 hours. The residue was used without further manipulation.

(Ii)

6- (3-phthalamidophenylsulfanyl) -3-iodo-1H-indazole was converted to 6- (3-phthalamidophenylsulfanyl) -3-styryl-1H-indazole as described in Example 11, step (iii). ¹ H NMR (300 MHz, CDCl 3) δ 7.93 (m, 3H), 7.78 (m 2H), 7.7 (s, 1H), 7.58 (m, 2H), 7.77-7 26 (m, 10H), 5.71 (s, 2H), 3.59 (t, 2H, J = 8.2 Hz), 0.89 (t, 2H, J = 8.2 Hz); 0.06 (s, 9H), HRMS (FAB) [M + Cs] / z calcd 736.1066, found 736.1058.

(Iii)

121

To a solution of 121 mg (0.2 mmol) of 6- (3-phthalamidophenylsulfanyl) -

3-Styryl-1H-indazole in 3.5 mL of ethanol was added 63 μΐ (2.0 mmol) of 10 eq) hydrazine. The reaction mixture was allowed to stir at 23 ° C for 45 minutes and was diluted with saturated sodium bicarbonate and ethyl acetate. The organic material was dried over sodium sulfate, decanted and concentrated.

Purification by silica gel chromatography (ethyl acetate / hexane 3: 7) afforded 79 mg (90%) of 6- (3-aminophenylsulfanyl) -3-styryl-1H-indazole as an oil: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.92 (d, 1H, J = 8.5Hz), 7.57 (m, 3H), 7.49 (d, 1H, J = 16.8Hz), 7.4-7.25 (m, 4H) 7.23 (dd, 1H, J = 1.5,8.5)

Hz), 7.11 (t, 1H, J = 7.9Hz), 6.79 (m, 1H), 6.70 (t, 1H, J =

1.9 Hz), 6.59 (m, 1H), 5.66 (s, 2H), 3.60 (bs, 2H), 3.59 (t,

2H, J = 8.2 Hz), 0.90 (t, 2H, J = 8.2 Hz), -0.05 (s, 9H), HRMS (FAB) [M + H] / z calcd 474, 2035, measured 474.2019.

(Iv)

To a solution of 43.7 mg (0.10 mmol) of 6- (3-aminophenylsulfanyl) -3-styryl-1H-indazole in 0.5 mL of dichloromethane was added 81 μΐ (1.0 mmol, 10 eq.) Of pyridine and 47 μΐ ( 0.5 mmol, 5 eq) acetic anhydride. The mixture was allowed to stir at 23 ° C for 10 minutes. The mixture was diluted with water and the product was extracted with 30% hexane in ethyl acetate. The organic material was washed with 5% citric acid and saturated bicarbonate

122 sodium. The organic material was dried over sodium sulfate, decanted and concentrated. Purification by silica gel chromatography (ethyl acetate / hexane 3: 7) gave 50 mg (97%) of 6- (3-acetamidophenylsulfanyl) -3-styryl-1H-indazole as an oil: R f sm 0.33, R _f p 0.18 (3: 7 ethyl acetate / hexane), 1 H NMR (300 MHz, CDCl ₃ ) δ 7.94 (d, 1H), 7.65-7.1 (m, 13H),

5.70 (s, 2H), 3.62 (t, 2H, J = 8.2 Hz), 2.18 (s, 3H), 0.93 (t, 2H, J = 8.2 Hz), -0.05 (s, 9H). HRMS (FAB) [M + Cs] / z calcd. 648.1117, found 648.1098.

Example 20 (b)

6- (3- (benzoylamido) phenylsulfanyl) -3-styryl-1H-indazole

The title compound was prepared as in Example 20 (a) except that benzoyl chloride was used instead of acetic anhydride in step (iv). ¹ H NMR (300 MHz, CDCl 3) δ 8.03 (s, 1H), 7.73 (d, 1H, J = 8.5 Hz), 7.63 (m, 2H), 7.47 (m, 1H),

7.42 (t, 1H, J = 1.9 Hz), 7.37 (m, 3H), 7.31 (m, 1H), 7.286.98 (m, 9H), HRMS (FAB) [M +] H] / z calcd. 448.1484, found 448.1490.

Example 21

6- (1- (3-aminophenyl) vinyl) -3-styryl-1H-indazole

123

6- (1- (3-Aminophenyl) vinyl) -3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole was converted to 85 mg (85%) of the title compound as described in the Example 11: R _f sm 0.72, p 0.37 (1: 1 ethyl acetate: hexane), FTIR (thin film) 3385, 3169, 2953, 1621, 1581, 1489, 1447, 1349, 1251,

1165, 1071, 959, 906, 870, 817 cm ^-1 , 1 H (300 MHz, CDCl ₃ ) δ 7.98 (d, 1H, J = 8.5 Hz), 7.60 (m, 2H), 7 51 (s, 1H), 7.48 (s, 1H), 7.40 (m, 3H), 7.29 (m, 2H), 7.15 (m, 1H), 6.78 (m, 1H), 6.68 (m, 2H), 5.50 (s, 2H), 3.65 (bs, 2H), MS (ES) [M + H] / z calcd 338, found 338, MS ( ES) [MH] / z calc. 336, measured 336.

The starting material was prepared as follows:

(I)

To a solution of 330 mg (0.693 mmol) of 6-iodo-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -4-indazole prepared in Example 14, step (i), in 3.0 mL of THF was at -78 0.56 ml (1.2 eq.) Of 1.5M n-butyllithium was added at 0 ° C. After 20 minutes, this solution was then added to 170 mg of anhydrous zinc chloride and the mixture was warmed to 23 ° C and stirred for 15 minutes. To this mixture was added 146 μΐ (1.05 eq.) Of 1- (3-nitrophenyl) vinyltriflate and 40 mg (0.05 eq.) Of Pd (PPh ₃ ) ₄ . The mixture was stirred for 30 minutes, partitioned between ethyl acetate and saturated sodium bicarbonate, and the organic layer was separated. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (ethyl acetate / hexane 1: 9) then a second column (1% ethyl acetate-benzene) gave 180 mg (52%) of 6- (1- (3-nitrophenyl) vinyl) -3-styryl-1- [2 (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole as an oil: FTIR

124

(thin film) 2951, 1616 1530 1477 1448 7305, 1248, 1217, 1077 961, 913, 859 cm ^-1 , 1H (300MHz, CDCl 3) □ 8.26 (t, 1H, J = 1.9 Hz), 8 , 21 m 1H), 8.00 (d, 1 H, J = 8.5 Hz), 7.69 (dt, 1 H, J = = 1.4, 7,8), 7 , 62-7 28 (m. 9H), 7 19 (dd, 1 H, J = 1.4, 8.4 Hz) , 5.72 (s, 3H) 5.69 (s, 1H); 60 (t, 2H, J = 8.2) Hz), 0.89 (t , 2H, J = 8.2 Hz), -0.05 (s, 9H) F ¹³ C NMR (75 MHz,

CDC1 ₃ ) δ 149, 9, 149, 6, 144.7, 144.5, 142.8, 140, 7, 138, 6,

135, 6, 133, 1, 130, 7, 130, 2, 129, 4, 128, 0, 124.4, 124.2, 124.1,

123, 8, 122, 6, 121.2, 118, 9, 111, 0, 79.2, 68, 0, 19.2, 0, 0, HRMS (FAB) [M + Na] / z calcd 520, 2031, measured 520.2046.

(Ii)

6- (1- (3-nitrophenyl) vinyl) -3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole was converted to 6- (1- (3aminophenyl) vinyl) -3-styryl-1 - [2- (trimethylsilanyl) ethoxymethyl] ind-indazole, as described in Example 11, step (iv) 140 mg (95%): R f sm 0.59, p 0.46 (ethyl acetate-hexane mixture)

4: 6),

FTIR (thin film) 3460, 3366, 3223, 3084, 3028 2952 2894. 2246 1616 1601 1581 1489 1474 1448 1359. 1303, 1249 1217, 1076 961 909 860 836 733,692 cm ' @ ¹ H NMR (300 MHz, CDCl3) .delta MHz CDCl3) δ 7.96 (d, 1H, J = 8.5 Hz), 7.59 (m, 3H), 7.50 (s, 1H), 7.46 (s, 1H); 7.40 (m, 2H); 30 (m, 1 H), 7.25 (m, IH); 7.14

(m, 1H), 6.77 (m, 1H), 6.68 (m, 2H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ

151.6. 147.7, 144.6. 143.9. 142.8. 130.2. 129.3. 128.0. 124.4. 123.6, 116.1. 110.8. 79.0. 67.9. 19.2.

142.4, 138.6, 132.8, 130.6,

121.9, 121.5, 120.2, 116.4,

0.0, HRMS (FAB) [M + Na] / z calcd 490.2291, found 490.2302.

125

Example 22 (a)

6- (1- (3- (5-methylthiaxol-2-carboxoylamido) phenyl) vinyl) -3-styryl-1H-indazole

6- (1- (3-aminophenyl) vinyl) -3-styryl-1H-indazolbol converted to 20 mg (72%) of the title compound as described in Example 12 (d): FTIR (thin film) 3271, 1673

1605, 1585, 1538, 1486, 1428, 1349, 1304, 1090, 960, 907, 871 cm ^-1; H NMR (300 MHz, CDC1 ₃₎ δ 10.7 (br s, 1H), 9.09 ( s, 1H)

8.0 (d, 1H); 7.79 (m, 1H); 7.60 (m, 3H); 7.51 (m, 3H);

7.15 (m, 7H), 5.59 (s, 2H), 2.54 (s, 3H), ¹³ C NMR (75 MHz, CDCl 3) δ 162, 2, 157, 9, 149, 8, 144 , 4, 142, 8, 142, 141

141.5, 140, 6, 137, 63, 137.56, 131, 6, 129, 5, 129, 1, 128.3,

126, 9, 125.1, 122, 6, 121.2, 120, 9, 120, 5, 120, 2, 119, 8, 116, 1,

110.2, 12.8, HRMS (FAB) [M + H] / z calcd 463.1593, found

463.1582.

Example 22 (b)

6- (1- (3- (Benzoylamido) phenyl) -vinyl) -3-styryl-lH-indazole

compound

prepared from Example 22 (b)

22 (a) except as described in the example similar to the use of benzoyl chloride in place of

5-methylthiazole-2-carboxylic acid and HATU. FTIR 3243, 1651,

1606, 1580, 1538, 1485, 1447, 1428, 1349, 1307, 1258, 1073,

126

959, 907 cm ^1; H NMR (300 MHz, CDC1 ₃₎ δ 9.09 (s, 1H), 7.99 (d, 1 H, J = 8.5 Hz), 7.78 (m, 1H) 7.60 (m, 3H); 7.51 (m, 3H);

7.43-7.15 (m, 10H), 5.56 (d, 2H, J = 3.2 Hz), ¹³ C NMR (75 MHz, CDCl 3) δ 166, 5, 149.7, 144.3 , 142.7, 142.1, 140, 6, 138.1, 137, 6, 135, 0, 132.3, 131, 6, 129, 4, 129, 1, 128, 3, 127, 4, 126 , 9, 125, 0, 122.5, 120, 9, 120, 8, 120, 6, 120, 5, 115, 9, 110, 2, HRMS (FAB) [M + H] / z calcd 442.1919 Measured 442.1919.

Example 22 (c)

6- (1- (3- (Benzoylamido) phenyl) -vinyl) -3-styryl-lH-indazole

The title compound was prepared in a similar manner to that described in Example 22 (a) except that carbobenzyloxy chloride was used in place of 5-methylthiazole-2-carboxylic acid and HATU. FTIR (thin film) 3305, 1712,

1606, 1586, 1537, 1487, 1445, 1348, 1216, 1059, 959, 908 cm ^-1; H NMR (300 MHz, CDCl3) δ 7.99 (d, 1 H, J = 8.5 Hz), 7 , 6-7.0 (m, 18H), 5.55 (s, 2H), 5.19 (s, 2H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ

153, 9, 149, 8, 144.3, 142, 7, 142, 1, 140, 7, 138.2, 137, 6, 136, 3,

131.7, 129.4, 129, 1, 129, 0, 128.7, 128.7, 128.3, 126, 9, 124.0,

122, 6, 121, 1, 120, 8, 120, 4, 115, 9, 110, 1, 67.4; HRMS (FAB) [M + H] / z calcd 472.025, found 472.2026.

Example 23

6- (1- (3-acetamidophenyl) -vinyl) -3-styryl-lH-indazole

127

6- (1- (3-acetamidophenyl) vinyl) -3-styryl-1- [2-trimethylsilanylethoxymethyl] -1H-indazole was converted to 6- (1- (3-acetamidophenyl) vinyl) -3-styryl-1H-indazole, as described for Example 11: FTIR (thin film) 3252, 1667, 1606, 1557, 1486 cm ^-1; H NMR (300 MHz, CDC1 ₃₎ δ 10.4 (br s, IH), 7.91 ( d, 1 H, J =

8.5 Hz), 7.5-7.0 (m, 13H), 5.47 (s, 2H), 2.10 (s, 3H), MS (ES) [M + H] / z calcd 380 found 380, [MH] / z calc. 378, measured 378.

The starting material was prepared as follows:

6- (1- (3-Aminophenyl) vinyl) -3-styryl-1- [2-trimethylsilanylethoxymethyl] -4-indazole was converted to 6- (1- (3-acetamidophenyl) vinyl) -3-styryl-1- [2-trimethylsilanylethoxymethyl] -1H-indazole as described in Example 12 (a): R _f sm 0.42, p 0.26 (ethyl acetate / hexane 4: 6), FTIR (thin film) 3305, 3059, 2952, 1667, 1608, 1585, 1555, 1486, 1448, 1433, 1369, 1306,

1249, 1076, 912, 859, 836, 748, 693 cm ^-1; H NMR (30Ω MHz.

CDCl 3) δ 7.98 (d, 1H, J = 8.5 Hz), 7.7-7.4 (m, 9H), 7.35 (m, 2H), 7.26 (dd, 1H, J = 1.3, 8.4 Hz), 7.16 (bd, 1H, J = 7.8 Hz), 5.75 (s, 2H), 5.62 (s, 1H), 5.61 (s 1 H, 3.66 (t, 2H, J = 8.2 Hz), 2.16 (s, 3H), 0.98 (t, 2H, J = 8.2 Hz), -0.02 ( with,

9H), ¹³ C NMR (75 MHz, CDCl ₃ ) δ 169.8, 150.9, 144.6, 143.5,

142.8, 142, 0, 139, 4, 138, 6, 132.9, 130, 3, 129, 3, 127, 9, 125, 6,

124.2, 123, 7, 122, 0, 121.3, 121.0, 117, 1, 110, 8, 68, 0, 25, 8,

128

19.1, 0.0, HRMS (FAB) [M + Na] / z calcd 532.2396, measured

532.2410.

Example 24 (a)

4- [3- (1-H-benzimidazol-2-yl) -1H-indazol-6-yl] -2-methoxy-5-methylphenol

326 mg (0.43 mmol) of 6- {5-methoxy-2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenyl} -1- [2- (trimethylsilanyl) ethoxymethyl] -

3- {1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzamidazol-2-yl} -1Hindazole was stirred in 4.5 mL of a 1M solution of TBAF in THF, which was concentrated in vacuo to 2.5 mL, and 0 1.6 ml (8.9 mmol) of ethylenediamine at reflux for 40 hours. The reaction was diluted with 40 mL / 5 mL of ethyl acetate-THF and washed with 20 mL H ₂ O and 20 mL brine. The organic layers were dried (MgSO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (60% THF / hexane) followed by precipitation from chloroform gave 108 mg (68%) of 4- [3- (1-H-benzimidazol-2-yl) -1H-indazol-6-yl] - 2-methoxy-5-methylphenol as a white solid. ¹ H NMR (300 MHz, DMSO-d 6) δ 13.62 (s, 1H), 13.05 (bs, 1H), 9.01 (s, 1H), 8.50 (d, 1H, J = 8.4 Hz), 7.62 (bs, 2H), 7.49 (s, 1H), 7.28-7, 20 (m, 3H), 6.85 (s, 1H), 6.74 (s, 1H), 3.77 (s, 3H), 2.15 (s, 3H). Anal. (C ₂₂ H ₁₈ N ₄ O ₂ · 1.3H

C, H, N. Calcd. C, 67.10; H, 5.27; N, 14.23. Measured: C,

67.30, H, 5.27, N, 14.11.

The starting materials were prepared as follows:

(I)

129

1) frBuLi.THF

«) H

Preparation of 2-iodo-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazole. A solution of 5.029 g (20.25 mmol) of 1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazole (see Witten et al., J. Org. Chem., 51, 1891-1894 1986) in 50 mL of THF was cooled at 78 ° C and added dropwise over 12 minutes via cannula to a flask containing 12.2 mL of 2.5M n-butyllithium in hexane, in 30 mL of THF at -78 ° C under an argon atmosphere. After stirring for 25 minutes at -78 ° C, the flask was warmed to 0 ° C for 10 minutes, then re-cooled to -7 ° C. This solution was then added via cannula to a second flask containing 25.7 g (101 mmol) of iodine in 50 mL of THF at -78 ° C. As the addition was complete (~ 5 minutes), the cooling bath was removed and stirring was continued for 30 minutes. The reaction mixture was partitioned between 500 mL of ethyl acetate and 100 mL of water. The organic layer was washed with 2 x 100 mL saturated aqueous sodium metabisulfite to remove the dark color of iodine, dried (MgSO 4) and concentrated in vacuo. Purification by flash chromatography (10% to 50% ethyl acetate / hexane) gave 4.79 g (63%) of pure 2-iodo-1- [2- (trimethylsilanyl) ethoxymethyl] -4-benzimidazole as a yellow solid. ¹ H NMR (300 MHz, CDCl 3) δ 7.76-7.72 (m,

1H), 7.54-7.51 (m, 1H), 7.29-7.25 (m, 2H), 5.54 (s, 2H), 3.59 (t, 2H, J = 8, 1 Hz), 0.92 (t, 2H, J = 8.1 Hz), -0.03 (s, 9H).

Anal. (C13H19IN2OS) C, H. Calcd C, 41.71, H, 5.12, I, 33, 90, N, 7.48. Found: C, 41.90, H, 5.09, I, 34.00, N, 7.37.

(Ii)

130

Preparation of 6-nitro-1- [2- (trimethylsilanyl) ethoxymethyl] -3 (trimethylstannanyl) -1H-indazole: 10.0 g (23.9 mmol) of 3-iodo-6-nitro-1- [2- (trimethylsilanyl) ethoxymethyl] 1 H-indazole and 10.0 g (30.5 mmol) of hexamethyldicin were placed in 45 mL dry toluene in an argon bubbling flask. 300 mg (0.26 mmol) of tetrakis (triphenylphosphine) palladium (0) were added and the reaction was refluxed under argon for 2.5 hours. The reaction was cooled to 23 ° C and diluted with 60 mL of ether. The organic layers were washed with 20 mL 0.1 N HCl and 20 mL brine, dried (MgSO ₄ ) and concentrated. Purification by silica gel chromatography (3% to 8% ether / hexane) gave 7.70 g (71%) of 6-nitro-1- [2- (trimethylsilanyl) ethoxymethyl] -3- (trimethylstannanyl) -1H-indazole as a light yellow

solid. ^r H NMR (300 MHz, CDCl ₃ ) δ 8.53 (D, IH, J = 1.8 Hz), 8.03 (dd, 1H, J = 8.7, 1.8 Hz), 7.81 (d, IH, J = 8 7 Hz), 5.84 (s, 2H). 3.58 (t, 2 H, J = 8.1 Hz), 0.90 (T, 2H, J = 8.1 Hz), 0.50 (t 9H, J = 28.2 Hz), -0.05 (with, 9H) • Anal. (C ₆ H 7 N ₃ O3SiSn ₂₎ C, H, N. Calcd my C, 42.13, H , 5, 97 N, 9.21.

Found: C, 42.39, H, 6.01, N, 9.26.

(Iii)

Preparation of 6-nitro-1- [2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazol-2-yl} -1H-inda

131 zole: 7.50 g (16.4 mmol) of 6-nitro-1- [2- (trimethylsilanyl) ethoxymethyl] -3- (trimethylstannanyl) -1H-indazole, 6.50 g (17.4 mmol)

3-Iodo-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazole and 313 mg (1.64 mmol) of copper (I) iodide were placed in 150 mL of dry THF in an argon bubbling flask. Tetrakis (triphenylphosphine) palladium (0) was added and the reaction stirred at reflux under argon for 23 hours. The reaction was cooled and adsorbed directly on silica gel (1616 g). Purification by silica gel chromatography (4% to 15% ethyl acetate / hexane) gave 7.28 g (82%) of 6-nitro-1- [2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (dimethylsilanyl) ethoxymethyl] 1 H-benzimidazol-2-yl] -1 H -indazole as a light yellow solid. ¹ H NMR (300 MHz, CDCl 3) δ 8.91 (d, 1H, J = 9.0 Hz), 8.59 (d, 1H, J = 1.8 Hz), 8.22 (dd, 1H, J = 8.7, 1.8 Hz), 7.92-7.89 (m, 1H), 7.66-7.62 (m, 1H), 7.40-

7.36 (m, 2H), 6.24 (s, 2H), 5.90 (s, 2H), 3.68-3.59 (m, 4H), 0.94 (t, 2H, J = 8.1 Hz), 0.86 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H), -0.15 (s, 9H). Anal. (C 6 H _{3 2} 7 N ₅ O ₄ Si 2) C, H, N. Calculated: C, 57.85, H, 6.91, N, 12,97.Namerané: C, 57 60; H, 6.81; N,

12.82.

(Iv)

Preparation of 6-amino-1- [2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazol-2-yl} -1H-indazole: 12.0 g (63.3) mmol) of tin (II) chloride was added to a solution of 7.18 g (13.3 mmol) of 6-nitro-1- (2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazole-2 -yl} -ΙΗ-indazole in 160 mL / 10 mL of DMF / H ₂ O a

The 132 reaction was stirred at 50 ° C for 2.5 hours. The reaction was cooled to 0 ° C and saturated sodium bicarbonate was slowly added, with stirring, until all the foam from the reaction had stopped. The material was concentrated in vacuo and taken up in 100 mL of ether. The insoluble material was removed by filtration and washed with 50 mL of ether. The filtrate was washed with 50 ml of brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (25% ethyl acetate / hexane) gave 6.05 g (89%) of 6-amino-1- [2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (trimethylsilanyl) ethoxymethyl] -1H -benzimidazol-2-yl} -1H-indazole as a light yellow waxy solid. ^X H NMR (300 MHz, CDCl3) δ 8.40 (d, 1 H, J = 9.0 Hz), 7, 89-7, 86 (m, 1 H), 7. 63-7. 60 (m, 1 H ), 7.35-7.31 (m,

2H), 6.78 (dd, 1H, J = 8.7, 1.8 Hz), 6.75 (s, 1H), 6.25 (s,

2H), 5.69 (s, 2H), 3.93 (bs, 2H), 3.65-355 (m, 4H), 0.93 (t,

2H, J = 8.1 Hz), 0.85 (t, 2H, J = 8.1 Hz), -0.04 (s, 9H), 0.15 (s, 9H). Anal. (C ₂₆ H ₃₉ N ₅ O ₂ Si ₂ ) C, H, N. Calcd C, 61.26, H, 7.71, N, 13.74. Found: C, 61.18, H, 7.65, N, 13.82.

133 (v)

Preparation of 6-iodo-1- [2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazol-2-yl} -1H-indazole: 500 mg solution (0.98 mmol) ) 6-Amino-1- [2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazol-2-yl} -1H-indazole in 1.5 ml acetic acid was diluted 1 1.0 mL of H 2 O and stirred at 0 ° C. 250 μΐ (~ 3 mmol) of concentrated HCl 250 μΐ in H ₂ O was added. 90 mg (1.3 mmol) of sodium nitrate in 300 μΐ H ₂ O was added and the reaction was stirred for 8 minutes. 10 mg of iodine and a solution of 250 mg (1.3 mmol) of potassium iodide in 250 μΐ H ₂ O were added and the foaming reaction was stirred for 30 minutes at 23 ° C. The reaction was diluted with 25 mL H ₂ O and extracted with 2 x 20 mL ethyl acetate. The organic layers were washed with 10 mL saturated sodium metabisulfite solution and 10 mL brine, dried (Na ₂ SO ₄ ), and concentrated in vacuo. Purification by silica gel chromatography (8% ethyl acetate / hexane) gave 316 mg (52%) of 6-iodo-1- [2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazole- 2-yl} -1H-indazole as a pale yellow oil which slowly crystallized to a white solid. ¹ H NMR (300 MHz, CDCl 3) δ 8.45 (d, 1H, J = 9.0 Hz), 8.05 (s, 1H), 7.91-7.88 (m, 1H), 7, 67-7.62 (m, 2H), 7.38-7.34 (m, 2H), 6.24 (s, 2H), 5.77 (s, 2H), 3.65-3.57 ( m, 4H), 0.93 (t, 2H, J = 8.1 Hz), 0.85 (t,

2H, J = 8.1 Hz), -0.04 (s, 9H), -0.15 (s, 9H). Anal.

(C 26 H 37 N ₄ O ₂ Si ₂ ) C, H, N. Calcd C, 50.31, H, 6.01, N, 9.03. Found: C, 50.55, H, 6.08, N, 9.00.

134 (vi)

Preparation of [2- (4-bromo-2-methoxy-5-methylphenoxymethoxy) ethyl] -

trimethylsilane: 4-bromo-2-methoxy-5-methylphenol (see Chien-Hsun

et al., Syn. Lett., 12, 1351-1352, 1997) was stirred in 100 mL of dry CH 2 Cl 2 at 23 ° C. 6.05 mL (34.6 mmol) of DIELA was added, followed by 5.6 mL (31.7 mmol) of 2- (trimethylsilyl) ethoxymethyl chloride. After stirring for 1 hour, the solution was washed

H ₂ O, 0.1N HCl, H ₂ O, saturated NaHCO ₃ and

The organic layers were dried (Na ₂ SO ₄ ) in vacuo. Purification by brine chromatography, 25 ml each.

and concentrated in silica gel (6% ethyl acetate-hexane) gave 9.06 g of 5-methoxy-phenoxymethoxy) -ethyl] -trimethyl-silane (91%) of [2- (4-bromo-2: As clear ^{oil.; H} NMR (300

MHz, CDCl 3) δ 7.06 (s, 1H),

7.02 (s, 1H).

3.84 (s, 3H); 3.79 (t, 2H, J = 8.4)

Hz),

2.31 (s,

3H), 0.96 (t,

2H,

8.4 (Hz), 0.01 (s, 9H).

(Vii)

Preparation of 5-methoxy-2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid: 2.6 g (7.5 mmol) of [2- (4-bromo-2-methoxy-5-methylphenoxymethoxy) ethyl] trimethylsilane was stirred in 10 mL dry TFA at -78 ° C under an argon atmosphere. 3.75 mL (9.36 mmol) of 2.5M n-butyllithium in hexane was added dropwise, and the reaction was stirred for 30 minutes before being transferred via cannula to a 8.4 mL (75 mmol) flask.

135 trimethylborate in 15 mL of THF, which was also stirred at -78 ° C under argon. After the addition was complete, the reaction was stirred for 30 minutes at -78 ° C, and then for 30 minutes while warming to 0 ° C. The reaction was then quenched with 20 mL H ₂ O, acidified with 0.1 N HCl and extracted with 2 x 25 mL ethyl acetate. The organic layers were washed with 20 mL brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (20% to 50% ethyl acetate / hexane) gave

1.11 g (47%) of 5-methoxy-2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid as a white solid. ^T H NMR (300 MHz, CDC1 ₃₎ delta 7.78 (s, 1H), 7.10 (s, 1H), 5.36 (s, 2H);

3.93 (s, 3H), 3.83 (t, 2H, J = 8.4 Hz), 2.79 (s, 3H), 0.98 (t, 2H, J = 8.4 Hz), 0.01 (s, 9H). Anal. (C ₁₄ H 25 BO _with Si-H ₂ O) C, H.

Calcd C, 57.15, H, 7.88. Found: C, 56.89, H, 7.87.

(Viii)

-t

Preparation of 6- {5-methoxy-2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenyl} -1- [2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (trimethylsilanyl) ethoxymethyl] - H-benzimidazo1-2-yl} -lH-indazole. 350 mg (0.56 mmol) of 6-iodo-1- [2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazol-2-yl} -1H-indazole, 211 mg (0.68 mmol) of 5-methoxy-2-methyl-4- [2 (trimethylsilanyl) ethoxymethoxy] phenylboronic acid and 72 mg (0.68 mmol) of sodium carbonate were stirred in a mixture of 5 ml of benzene, 330 μΐ H ₂ O and 1 ml of methanol in a bubbling flask

136 with argon. Tetrakis (triphenylphosphine) palladium (0) was added and the reaction was stirred at reflux under argon for 16 hours. After cooling to 23 ° C, the reaction was diluted with 20 mL of ether, washed with 10 mL of H ₂ O and 10 mL of brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (15% ethyl acetate / hexane) afforded 382 mg (89%) of 6- {5-methoxy-2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenyl} -1- [2- (trimethylsilanyl) ) ethoxymethyl] -

3- {1- [2- (trimethylsilanyl) ethoxymethyl] -lH-benzimidazol-2-yl} -lH-

indazole than white solid substances. ¹ H NMR (300 MHZ, CDC1 ₃ ,) δ 8.68 (D, 1H, J = 8.4 Hz), 7.93-7.90 (M, 1H), 7, 67- -7, 63 (M, 1H), 7.54 (with, 1H), 7, 38-7.32 (m, 3H) 7, 13 (with, 1H), 6, 86 (s, 1H), 6.29 (with, 2H), 5.83 (s, 2H), 5.34 (with, 2H), 3, 89 (s, 3H) 3, 86 (T, 2H, J = 8.4 Hz), 3.69 to 3.58 (M, 4H), 2.22 (with, 3H),

1.01 (t, 2H, J = 8.4 Hz), 0.95-0.83 (m, 4H), 0.03 (s, 9H), 0.05 (s, 9H), -0, 15 (s, 9H). Anal. (C ₄₀ H _{60 N 4} O ₅ Si 3) C, H, N. Calcd C, 63.12, H, 7.95, N, 7.36. Found: C, 63.22, H, 7.93, N, 7.46.

Example 24 (b)

4- [3- (l-H-benzoimidazol-2-yl) -lH-indazol-6-yl] -3-methylphenol

TBAF ------ > ttiyfomdlwil M THF, reflux, 40h

To prepare the title compound, the procedure described in Example 24 (a) was followed, wherein 2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid (prepared as described below) was used in place of 5-methoxy-2. methyl-4- [2

137 (trimethylsilanyl) ethoxymethoxy] phenylboronic acid in step (viii). ^X H NMR (300 MHz, _DMSO-d6) δ 13.60 (s, 1H), 12.99 (br s, 1H), 9.41 (s, 1H), 8.49 (d, 1 H, J = 8.4 Hz), 7.72 (bs, 1H),

7.52 (bs, 1H), 7.45 (s, 1H), 7.25-7.21 (m, 3H), 7.12 (d, 1H, J = 8.1 Hz), 6, 73-6, 67 (m, 2H), 2.20 (s, 3H). Anal. (C ₂ H ₁₆ N ₄ O · 0.7 H ₂ O) C, H, N. Calculated: C, 71.45, H, 4.97, N, 15.87. Found: C, 71.44, H, 4.96, N, 15.77.

2-Methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid was prepared as follows:

(i) [2- (4-Bromo-3-methylphenoxymethoxy) ethyl] trimethylsilane was prepared in 86% yield from 4-bromo-3-methylphenol according to the procedure for [2- (4-bromo-2-methoxy-5-methylphenoxymethoxy) ) ethyl] trimethylsilane. ^X H NMR (300 MHz, CDC1 ₃₎ δ 7.39 (d, 1 H, J = 8.7 Hz), 6.93 (d, 1 H, J = 2.7 Hz), 6.75 (dd, 1 H , J = 8.7, 2.7 Hz),

5.16 (s, 2H), 3.74 (t, 2H, J = 8.4 Hz), 2.36 (s, 3H), 0.95 (t, 2H, J = 8.4 Hz), 0.01 (s, 9H). Anal. (C ₃ H ₂₁ BrO ₂ Si) C, H

Calcd C, 49.21, H, 6.67. Found: C, 49.33, H, 6.67.

(Ii)

3) Η, Ο

PULL

2-Methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid was prepared in 52% yield from [2- (4-bromo-3-methylphenoxymethoxy) ethyl] trimethylsilane according to the procedure for 5138 methoxy-2-methyl-4- [2 - (trimethylsilanyl) ethoxymethoxy] phenylboronic acid listed above.

^X H NMR (300 MHz, CDC1 ₃₎ δ 8.15 (d,

1H, J = 8.1 Hz), 6.98-6.92 (m, 2H), 5.29 (s, 2H), 3.78 (t, 2H,

8.4 Hz), 2.78 (s, 3H),

0.98 (t, 2H, J = 8.4Hz), 0.01 (s,

9H). Anal. (C13H23BO4S1 - _H2O) C, H. Calculated: C, 59.10, H,

8.01. Found: C, 59.07, H, 8.08.

Example 24 (c)

4- [3- (1H-benzimidazol-2-yl) -1H-indazol-6-yl] -2-chloro-5-methylphenol

For the preparation of the title compound, 5-chloro-2-methyl-

4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid, prepared as described below, was used in place of 5-methoxy-2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid from the procedure described in Example 24 (a), step (viii). ¹ H NMR (300 MHz, DMSO-d 6) δ 13.61 (s, 1H), 13.00 (bs, 1H), 10.22 (s, 1H), 8.51 (d, 1H, J = 8.4 Hz), 7.64 (bs, 2H), 7.50 (s, 1H), 7.26-7.21 (m, 4H), 6.95 (s, 1H), 2.19 (s, 3 H).

5-Chloro-2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid was prepared as follows:

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139

6.68 g (46.9 mmol) of 2-chloro-5-methylphenol was stirred in 200 ml of acetonitrile. 8.5 g (47.8 mmol) of N-bromosuccinimide were added and the reaction was stirred for 45 minutes. The solution was concentrated in vacuo and redissolved in 100 mL of chloroform. The organic layers were washed with 50 mL saturated NaHCO 3 and 50 mL brine, dried (MgSO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (8% ethyl acetate / hexane) afforded 7.98 g (77%) of 4-bromo-3-chloro-5-methylphenol as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.47 (s, 1H), 6.91 (s, 1H), 5.52 (bs, 1H), 2.32 (s, 3H). Anal. (C ₇ H ₆ ClBrO · 0.1 H ₂ O) C, H. Calcd C, 37.66, H, 2.80. Found: C, 37.57, H, 2.82.

[2- (4-bromo-2-chloro-5-methylphenoxymethoxy) ethyl] trimethylsilane was prepared in 83% yield from 4-bromo-3-chloro-5-methylphenol according to the procedure for [2- (4-bromo-2- methoxy-5-methylphenoxymethoxy) ethyl] trimethylsilane. ¹ H NMR (300 MHz, CDCl ₃ ) δ

7.51 (s, 1H), 7.09 (s, 1H), 5.26 (s, 2H), 3.79 (t, 2H, J = 8.4 Hz), 2.35 (s, 3H) 0.95 (t, 2H, J = 8.4 Hz), 0.02 (s, 9H). Anal. (C ₃ H ₂ oClBr0 ₂ Si) C, H. Calculated: C, 44 39; H, 5.73. Found: C, 45.08, H, 5.91.

(Iii)

140., 1) BuU.THF

J --- - »2) B <OM ·), here») H1O

5-chloro-2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid was prepared in 54% yield from [2 (4-bromo-2-chloro-5-methylphenoxymethoxy) ethyl] trimethylsilane according to the procedure for 5 -methoxy-2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid. ¹ H NMR (300 MHz, CDCl 3) δ 8.11 (s, 1H), 7.09 (s, 1H), 5.37 (s, 2H), 3.84 (t, 2H, J = 8.4 Hz);

2.76 (s, 3H), 0.98 (t, 2H, J = 8.4 Hz), 0.01 (s, 9H). Anal. (C13H22BCIO4SÍ - _H2O) C, H. Calculated: C, 52.28, H, 6.75. Found: C, 51.98, H, 6.84.

Example 24 (d)

3-H-benzoimidazol-2-yl-6- (4-hydroxy-2-methoxy-phenyl) -lH-indazole

The compound of Example 24 (d) was prepared in a similar manner to that described in Example 24 (a) except that

4-bromo-3-methoxyphenol, prepared as described by Carreno et. Al., Syn. Lett., 11, 1241-42, 1997, was used in place of 4-bromo-2-methoxy-5-methylphenol in step (vi). ¹ H NMR (300 MHz, DMSO-d 6) δ 1352 (s, 1H), 12.98 (s, 1H), 9.63 (s, 1H),

8.44 (d, 1H, J = 8.4Hz), 7.72 (d, 1H, J = 6.9Hz), 7.61 (s, 1H), 7.50 (d, 1H, J) = 6.9 Hz), 7.36 (dd, 1 H, J = 8.4, 1.5 Hz), 7.18-7.22 (m, 3H), 6.55 (d, 1 H, J = 2.1 Hz), 6.48 (dd, 1H, J =

141

8.1, 2.1 Hz), 3.74 (s, 3H). MS (ES) [M + H] / z calc. 357, measured 357, [M-H] / z calc. 355, measured 355.

Example 24 (e)

3-H-benzoimidazol-2-yl-6- (2-ethyl-4-hydroxyphenyl) -lH-indazole

OH

The compound of Example 24 (e) was prepared in a similar manner to that described in Example 24 (a) except that

4-Bromo-3-ethyl-phenol, prepared in 80% yield according to the procedure described by Carreno et. Al., Syn. Lett., 11, 1241-42.

1997, for the synthesis of 4-bromo-3-methylphenol, was used instead

4-bromo-2-methoxy-5-methylphenol in step (vi). ¹ H NMR (300 MHz, DMSO-d 6) δ 13.66 (s, 1H), 13.02 (s, 1H), 9.43 (s, 1H), 8.49 (d, 1H, J = 8) 4 Hz), 7.72 (d, 1 H, J = 6.9 Hz), 7.53 (d, 1 H, J =

6.9 Hz), 7.44 (s, 1H, 7.18-7.25 (m, 3H)), 7.06 (d, 1H, J = 8.1

Hz), 6.75 (d, 1H, J = 2.1 Hz), 6.66 (dd, 1H, J = 8.1, 2.1 Hz),

2.50 (q, 2H, J = 7.5Hz), 1.04 (t, 3H, J = 7.5Hz). MS (ES) [M + H] / z calc 355, found 355, [M-H] / z calc 353, measured 353.

Example 24 (f)

3-1H-benzimidazol-2-yl-6- (2,4-dihydroxyphenyl) -1H-indazole

142

mg (0.13 mmol) of 6- (2-methoxy-4-hydroxyphenyl) -3-1H-benzimidazol-2-yl-1H-indazole prepared in Example 24 (d) was heated in 0.5 g of pyridinium chloride at 180 ° C for 2 hours. The reaction was allowed to cool and was quenched with 15 mL saturated NaHCO 3 and extracted with 2 x 20 mL EtOAc. The organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (60% THF / hexane) gave 26 mg (59%) of the title compound as a white solid.

white solid. ^r H NMR (300 MHz, DMSO-de) δ 13,49 (s, 1 H), 12.94 (s, 1H); 9.49 (with, 1H), 9.39 (s, 1H). 8.43 (d, 1 H, J = 8.4 Hz), 7.71 7.74 (M, 2H), 7.50 (d, 1H, J) = 6.9 Hz), 7.43 (dd, 1H, J = 8.4, 1, 2 Hz 7.16-7.23 (m, 3H); 6.45 (d, 1 H, J = 2.1 Hz), 6.35 (dd, 1H, J = 8.4, 2.1 Hz). MS (ES) (M + H] / z calcd. 343, measured 343, [M-H] / z calcd. 341, measured

341st

Example 24 (g)

3-H-benzoimidazol-2-yl-6- (2-phenoxy-4-hydroxyphenyl) -lH-indazole

The compound of Example 24 (g) was prepared in a similar manner to that described in Example 24 (c) except that

143

3-Phenoxyphenol was used in place of 2-chloro-5-methylphenol in step (i). ¹ H NMR (300 MHz, DMSO-d 6) δ 13.54 (s, 1H), 12.95

(with, 1H), 9.78 (s, 1H), 8, 43 (D, 1 H, J = 8, 4 Hz), 7.67-7.72 (m, 2H); 7.49 (dd, 1 H, J = 6/3, 2.1 Hz), 7.43 (d, 2H, J = 8.4Hz), 7.33 (T, 2H, J = 7.5 Hz), 7 17-7.22 m 2H), 6.96-7.07 (m, 3H); 6, 72 (dd, 1 H, J = 8.4. 2.1 Hz), 6.40 (d, 1H, J = 2.1Hz). MS (EC) [M + H] / z calculated 419, found 419, [M-H] / z

calculated 417, measured 417.

Example 24 (h)

3-H-benzoimidazol-2-yl-6- (2- (2-methoxyethyl) -4-hydroxyphenyl) H-indazole

Example 24 (h) was prepared in a manner similar to that described in Example 24 (a) except that {2- [4-bromo-3- (2-methoxyethyl) phenoxymethoxy] ethyl} trimethylsilane, prepared as described above below, instead of [2- (4-bromo-2-methoxy-5-methylphenoxymethoxy) ethyl] trimethylsilane was used in step (vii). ^{Χ Η} NMR (300 MHz, _DMSO-d6) δ 13.60 (s, 1H), 13.01 (s,

1H), 9.44 (s, 1H), 8.49 (d, 1H, J = 8.4 Hz), 7.73 (bs, 1H),

7.51 (bs, 1H), 7.46 (s, 1H), 7.21 (about d, 3H, J = 8.1

Hz), 7.09 (d, H, J = 8.1 Hz), 6.78 (d, 1H, J = 2.4 Hz), 6.70 (dd, 1H, J = 8.1, 2, 4 Hz), 3.40 (t, 2H, J = 7.2 Hz), 3.12 (s,

3H), 2.75 (t, 2H, J = 7.2Hz). MS (ES) [M + H] / z calc. 385, measured 385, [M-H] / z calc. 383, measured 383.

The starting material was prepared as follows:

(I)

144

4-Bromo-3- (2-hydroxyethyl) phenol was prepared in 88% yield by substituting 3- (2-hydroxyethyl) phenol in the procedure described in Example 24 (c), step (i). ¹ H NMR (300 MHz, CDCl 3) δ

9.56 (s, 1H), 7.29 (d, 1H, J = 8.7 Hz), 6.74 (d, 1H, J = 3.0 Hz), 6.55 (dd, 1H, J) = 8.7, 3.0 Hz), 4.71 (t, 1H, J = 5.4 Hz), 3.52-3.59 (m, 2H), 2.73 (t, 2H, J 7.2 Hz).

ii) OlEA.CHaÔa Y OH "'PULL

Preparation of 2- [2-bromo-5- (2-trimethylsilanylethoxymethoxy) phenyl]: was prepared in 65% yield by substituting 4-bromo-3- (2-hydroxyethyl) phenol according to the procedure described in Example 24 (a),

step (vi) . ^X H NMR (300 MHz, CDC1 ₃₎ δ 7.43 (d, 1 H, J = 8, 7 Hz), 6.97 (d, 1H, J = 3.0 Hz), 6.82 (dd, 1H, J = 8.7, 3.0 Hz) F 5.19 (s, 2H) 3.88 (q, 2H, J = 6.6 Hz), 3.74 (t, 2H, J = 8) 4 Hz), 2.99 (t, 2H, J = 6.6 Hz), 1.42 (t, 1H, J = 6. 6. Hz). 0 94 (T, 2H, J = 8 4 Hz), -0.01 (s, 9H).

(Iii)

145 {2- [4-Bromo-3- (2-methoxyethyl) phenoxymethoxy] ethyl} trimethylsilane: 1.9 g (6.0 mmol) of 2- [2-bromo-5- (2-trimethylsilanylethoxymethoxy) phenyl] ethanol was added to a solution of 1.35 g (24 mmol) of potassium hydroxide in 16 mL of DMSO. 1.12 mL (18 mmol) of iodomethane was added and the solution was stirred for 16 hours. The reaction was diluted with 50 mL of water and extracted with 2 x 40 mL of ether. The organic layers were washed with 40 mL of brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (10% ether / hexane) gave 1.28 g of {2- [4-bromo-3- (2-methoxyethyl) phenoxymethoxy] ethyl} trimethylsilane as a clear oil. ^{Σ Η} NMR (300 MHz, CDC1 ₃₎ δ 7.40 (d, 1 H, J = 8.7

Hz), 6, 96 (D, 1H, J = 3.0 Hz), 6.80 (Dd, 1H, J = 8.7, 3.0 Hz), 5.18 (with, 2H), 3.74 (t, 2H, J = 8.4) Hz), 3.60 (t, 2H, J = 7.2) Hz), 3.37 (with, 3H), 2.98 (t, 2H, J = 7.2 Hz), 0.95 (t, 2H, J = 8.4 Hz), · -0, 01 (s, 9H).

Example 24 <i)

3-1H-benzimidazol-2-yl-6- (2- (2-hydroxyethyl) -4-hydroxyphenyl) -1H-indazole

mg (0.26 mmol) of 3-1H-benzimidazol-2-yl-6- (2- (2-methoxyethyl) -4-hydroxyphenyl) -ΙΗ-indazole, from Example 24 (i), was dissolved in 20 mL of EtOAc and cooled to -78 ° C under an argon atmosphere. Boron tribromide was added dropwise and the reaction was allowed to stir while warming to room temperature over

146 for 3 hours. The solution was diluted with 60 mL EtOAc and washed with saturated NaHCO ₃ and brine, 20 mL each. The organic layers were dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (THF) gave 56 mg (59%) of the title compound as a white solid. ¹ H NMR (300 MHz, DMSO-d 6) δ 13.60 (s, 1H), 13.01 (s, 1H), 9.41 (s, 1H), 8.49 (d, 1H, J = 8) 4 Hz), 7.71 (bs, 1H), 7.51 (bs, 1H), 7.46 (s, 1H), 7.21 (about d, 3H, J = 8.1 Hz) 7.08 (d, 1H, J =

8.4 Hz), 6.77 (d, 1H, J = 2.1 Hz), 6.69 (dd, 1H, J = 8.1, 2.1 Hz), 4.57 (bs, 1H 1.46 (t, 2H, J = 7.2 Hz), 2.68 (t, 2H, J = 7.2 Hz). MS (ES) [M + H] / z calcd 371, found 371, [Μ-]

Η] / z calculated 369, measured 369.

Example 24 (j)

3-1H-benzimidazol-2-yl-6- (2,6-dimethyl-4-hydroxyphenyl) -1H-indazole

The compound of Example 24 (j) was prepared in a similar manner to that described in Example 24 (a) except that

4-Bromo-3,5-dimethylphenol was used instead

4-bromo-2-methoxy-

5-methylphenol in step (vi). ¹ H NMR (300 MHz, DMSO-d 6) δ 13.57 (s, 1H), 12.99 (s, 1H), 9.22 (s, 1H), 8.52 (d, 1H, J = 8) , 4

Hz), 7.72 (d, 1H, J = 6.6 Hz), 7.51 (d, 1H, J = 6.6 Hz), 7.31 (s, 1H), 7.16-7, 25 (m, 2H), 7.02 (d, 1H, J = 8.4Hz), 6.55 (s, 2H), 1.93 (s, 6H). MS (ES) [M + H] / z calc 355, found

355, [M-H] / z calcd 353, measured 353.

147

Example 24 (k)

3-1H-benzimidazol-2-yl-6- (2-methylsulfanyl-4-hydroxyphenyl) -1H-indazole

The compound of Example 24 (k) was prepared in a similar manner to that described in Example 24 (c) except that

The 3-methylsulfanylphenol, prepared as described below, was used in place of 2-chloro-5-methylphenol in step (i). ¹ H NMR (300 MHz, DMSO-d 6) δ 13.59 (s, 1H), 12.98 (s, 1H), 9.64 (s, 1H), 8.48 (d, 1H, J = 8) 4 Hz), 7.71 (bs, 1H), 7.52 (s, 2H), 7.20-7.27 (m, 3H), 7.12 (d, 1H, J = 8, 4 Hz), 6.76 (d, 1H, J = 2.1 Hz), 6.65 (dd, 1H, J = 8.4, 2.1 Hz), 2.34 (s, 3H). MS (ES) [M + H] / z calc. 373, measured 373, [MH] / z calc.

371, measured 371.

The starting material was prepared as follows:

(I)

acetone

Preparation of 3-methylsulfanylphenol..5.0 g (39.7 mmol)

Of 3-hydroxythiophenol and 6.03 g (43.6 mmol) of potassium carbonate were stirred in 80 ml of acetone at 0 ° C. 2.5 ml (40 mmol) of iodomethane were added dropwise and the reaction was stirred for 45 minutes. The solution was diluted with 150 mL H ₂ O and extracted

148 x 100 mL EtOAc. The organics were washed with 100 mL of brine, dried (NasSOJ and concentrated in vacuo. Purification by silica gel chromatography (25% EtOAc-hexane) afforded 5.08 g (91%) of 3-methylsulfanyl-phenol as a clear ^{oil.; H} NMR (300 MHz CDCl ₃ ) δ 7.15 (t, 1H, J = 8.1 Hz), 6.82 (d, 1H, J = 8.1 Hz), 6.74 (t, 1H, J = 1.8 Hz), 6.60 (dd, 1 H, J =

8.1, 1.8 Hz), 4.86 (s, 1H), 2.47 (s, 3H).

Example 24 (1)

3-H-benzoimidazol-2-yl-6- (2- (ethoxymethyl) -5-methoxy-4-hydroxyphenyl) -lH-indazole

The compound of Example 24 (1) was prepared in a manner similar to that described in Example 24 (a) except that [2- (4-bromo-5-ethoxymethyl-2-methoxyphenoxymethoxy) ethyl] trimethylsilane, prepared as described below , was used in place of [2- (4-bromo-2-methoxy-5-methylphenoxymethoxy) ethyl] trimethylsilane in step (vii). ^X H NMR (300 MHz, DMSO-de) δ 13.63 (s, 1H), 12.99

(s, 1H) 9.15 (s, 1H) 8.50 (d, 1H, J = 8.4Hz), 7.73 (dd, 1 H, J = 6.6, 2.1 Hz), 7, 59 (with, 1H), 7.51 (dd, 1 H, J = 6.6, 2.1 Hz), 7.32 (d, 1 H, J = θ / 4 Hz), 7.19- 7.24 (m, 2H). 6.94 (s, 1H), 6.91 (s, 1H). 4.22 (with, 2H), 3.81 (s, 3H) 3.39 (q, 2H, J) = 6.9 Hz), 1.13 (T, 3H, J = 6.9 Hz). MS (ES) [M + H] / z calcd 415, measured 415 •

The starting material was prepared as follows:

(I)

149

SEM-CI

ΟΙΕΑ, ΟΗ ^

2-Bromo-4-methoxy-5- (2-trimethylsilanylethoxymethoxy) benzaldehyde was prepared in 79% yield by substituting 4-bromo-3-formyl-2-methoxyphenol (Hazlet et al., J. Org. Chem., 27, 3253-). 55, 1962) in the procedure described in Example 24 (a), step (vi). ^X H NMR (300 MHz, CDC1 ₃₎ d 10.16 (s, IH), 7.68 (s, IH), 7.07 (s, IH), 5.28 (s, 2H), 3.94 (s, 3H), 3.77 (t, 2H, J = 8.4 Hz), 0.94 (t, 2H, J = 8.4 Hz), -0.03 (s, 9H).

(Ii)

DNaBH ^ MeQH

2) EH, KOH, DMSO

Preparation of [2- (4-bromo-5-ethoxymethyl-2-methoxyphenoxymethoxy) ethyl] trimethylsilane: 275 mg (7.2 mmol) of sodium borohydride was added in portions over 10 minutes to a solution of 1.3 g (3.6 mmol). 2-Bromo-4-methoxy-5- (2-trimethylsilanylethoxymethoxy) benzaldehyde in 20 mL of MeOH at 0 ° C. After 30 minutes, the reaction was diluted with 4Ό mL of H ₂ O and extracted with 2 x 30 mL of EtOAc. mL of brine, dried (Na ₂ SO ₄₎ and concentrated in vacuo to afford 1.31 g [2-bromo-4-methoxy-5- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -methanol a clear ^{oil.; H} NMR (300 MHz, CDC1 ₃₎ δ 7.29 (s, 1H), as

7.05 (s,

IH)

5.27 (s, 2H), 4.66 (d, 2H, J = 6.6 Hz), 3.87 (s, 3H),

3.79 (t, 2H, J = 8.4 Hz)

0.96 (t,

2H, J = 8.4 Hz), 0.01 (s,

9H).

150

The crude benzyl alcohol was stirred with a solution of 800 mg (14.4 mmol) of potassium hydroxide in 8 mL of DMSO. 580 mL (7.2 mmol) of iodoethane was added and the reaction was stirred for 16 hours before it was diluted with 30 mL of H ₂ O and extracted with 2 x 30 mL of ether. The organic layers were washed with 20 mL brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc / hexane) gave 1.30 g (92%) of the title compound as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.29 (s, 1H), 7.03 (s, 1H), 5.26 (s, 2H), 4.48 (s, 2H), 3.85 (s, 3H), 3.79 (t, 2H, J = 8.4Hz), 3.58 (q, 2H, J =

6.9 Hz), 1.26 (t, 3H, J = 6.9 Hz), 0.95 (t, 2H, J = 8.4 Hz), 0.01 (s, 9H).

Example 24 (m)

3-H-benzoimidazol-2-yl-6- (2- (hydroxymethyl) -4-ethoxy-5metoxyfenyl) -lH-indazole

The compound of Example 24 (m) was prepared in a similar manner to that described in Example 24 (a) except that [2- (2-bromo-5-ethoxy-4-methoxybenzyloxymethoxy) ethyl] trimethylsilane, prepared as described below , was used instead of [2- (4-bromo-2-methoxy-5-methylphenoxymethoxy) ethyl] trimethylsilane in step

(Vii) . ^X H NMR (300 MHz DMSO-de) δ 13,64 (s, IH) 13, 00 (with, IH), 8, 50 (D, IH, J = 8, 4 Hz) 73 (d, 1H) J = 8.4 Hz), 7, 62 (s, IH) 7, 52 (Dd, IH, J = 6.0, 1.8 Hz), 7.32 (dd, IH, J = 8.4. 1, 2 Hz), 7, 19- 7.24 (m, 2H) 7.15 (s, 1H), 6.91 (with, IH), 5, 11 (T, IH, J = 5, 1 Hz) 4.37 (d, 2H, J = = 5.1 Hz), 4, 08 (Q,

151

2Η, J = 6.9 Hz), 3.80 (s, 3H), 1.37 (t, 3H, J = 6.9 Hz). MS (ES) [M + H] / z calc. 415, found 415.

The starting material was prepared as follows:

(I)

Preparation of 4-bromo-2-methoxy-5- (2-trimethylsilanylethoxymethyl) phenol: [2-bromo-4-methoxy-5- (2-trimethylsilanylethoxymethoxy) phenyl] methanol, after one week of standing SEM migration from phenolic to benzyl alcohol to give the title compound. ^X H NMR (300 MHz, CDCl3) δ 7.04 (s,

1H), 7, 01 (with, 1H), 5.54 (s, 1H), 4.77 (s, 2H) , 4.57 (s, 2H) 3, 88 (with, 3H), 3, 68 (t, 2H, J) = 8.4 Hz) , 0.97 (t, 2H) J = 8.4 Hz); 0, 02 (with, 9H).

(Ii)

Preparation of [2- (2-bromo-5-ethoxy-4-methoxybenzyloxymethoxy) ethyl] trimethylsilane: 1.28 g (3.53 mmol) of 4-bromo-2-methoxy-5- (2-trimethylsilanylethoxymethyl) phenol was stirred with a solution of 790 mg (14.1 mmol) of potassium hydroxide in 8 mL of DMSO. 565 mL (7.1 mmol) of iodoethane was added and the reaction was stirred for 16 hours before it was diluted with 30 mL of H ₂ O and extracted with 2 x 30 mL of ether. The organic layers were washed with 20 mL brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification

152 chromatography on silica gel (15% EtOAc / hexane) gave 1.26 g (91%) of the title compound as a clear oil. ^X H NMR (300 MHz, CDC1 ₃₎ δ 7.02 (s, 1H), 6.98 (s, 1H).

4.78 (s, 2H), 4.60 (s, 2H), 4.09 (q, 2H, J = 6.6 Hz), 3.86 (s, 3H), 3.69 (t, 2H J = 8.4 Hz), 1.46 (t, 3H, J = 6.6 Hz), 0.97 (t, 2H, J = 8.4 Hz), 0.04 (s, 9H).

Example 24 (n)

3-H-benzoimidazol-2-yl-6- (2- (hydroxymethyl) -5-methoxy-4-hydroxyphenyl) -lH-indazole

OH .OH

OMe

The compound of Example 24 (n) was prepared in a similar manner to that described in Example 24 (a) except that

6- [5-methoxy-2-hydroxymethyl-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -3- [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazol-2-yl] -1H-indazole prepared as described below was used in place of 6- [5-methoxy-2-methyl-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -3- [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazole 2-yl] -ΙΗ-indazole. ^X H NMR (300 MHz, _DMSO-d6) δ

13.59 (s, 1 H), 12.95 (s, 1 H), 9.05 (s, 1 H), 8.49 (d, 1 H, J =

8.4 Hz), 7.72 (dd, 1H, J = 6.3, 2.1 Hz), 7.60 (s, 1H), 7.51 (dd, 1H, J = 6.3, 2) 1 Hz), 7.31 (d, 1H, J = 8.4 Hz), 7.20-7.24 (m, 2H), 7.02 (s, 1H), 6.87 (s, 1H) 5.02 (t, 1H, J = 5.4 Hz),

4.32 (d, 2H, J = 5.4 Hz); 3.80 (s, 3H). MS (ES) [M + H] / z calc 387, measured 387, [M-H] / z calc 385, measured 385.

153

The starting material was prepared as follows:

(I)

Preparation of 4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -2-trimethylstannanylbenzaldehyde: 3.36 g (9.3 mmol) of 2-bromo-4-methoxy-5- (2-trimethylsilanylethoxymethoxy) benzaldehyde and 5.0 g (15.3 mmol) hexamethyldicin was stirred in 60 mL dry toluene in an argon-bubbled flask. 500 mg (0.45 mmol) of tetrakis (triphenylphosphine) palladium (0) were added and the reaction was stirred at 100 ° C for 23 hours. The reaction was cooled and concentrated in vacuo. Purification by silica gel chromatography (5% EtOAc / hexane) gave 2.77 g (67%)

4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -2-trimethylstannanylbenzaldehyde as a clear oil. ¹ H NMR (300 MHz, CDCl 3, δ) 9.81 (dd, 1H, J = 3.0, 0.9 Hz), 7.66 (t, 1H, J = 6.6 Hz), 7.21 (t, 1H, J = 9.0 Hz), 5.35 (s, 2H), 3.99 (s, 3H),

3.82 (t, 2H, J = 8.4 Hz), 0.25 (t, 9H, J = 26.7 Hz), 0.98 (t, 2H, J = 8.4 Hz), -0 1.01 (s, 9H).

(Ii)

Preparation of [4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -2-trimethylstannanylphenyl] -methanol: 2.36 g (5.3 mmol) of 4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -2-trimethylstannanylbenzaldehyde

154 was stirred in 30 mL of MeOH at 0 ° C. 400 mg (10.6 mmol) of sodium borohydride was added and the reaction was stirred for 1 hour. The solution was diluted with 60 mL H ₂ O and extracted 2 x mL. EtOAc. The organic layers were washed with 50 mL brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo to give 2.16 g (91%) of [4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -2-trimethylstannanylphenyl] methanol as a clear oil. ³ H

NMR

MHz, CDCl ₃ ) δ 7.18 (t, 1H, J = 6.9 Hz), 7.03 (t, 1H,

9.3

Hz), 5.27 (s, 2H), 4.58-4.63 (m, 2H), 3.89 (s, 3H),

3.80 (t,

1.53 (t, 1H, J = 6.0)

Hz),

0.96 (t,

2H,

9H, J

27.3 (s,

9H).

(Iii)

Preparation of 6- [5-methoxy-2-hydroxymethyl-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -3 [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazol-2-yl] -1Hindazole : 300 mg (0.48 mmol) of 6-iodo-1- [2- (trimethylsilanyl) ethoxymethyl] -3- {1- [2- (trimethylsilanyl) ethoxymethyl] -1H-benzimidazol-2-yl} -1H-indazole [Example 24 (a), step (v)] and 282 mg (0.63 mmol) of [4-methoxy-5- (2-trimethylsilanylethoxymethoxy) -2-trimethylstannanylphenyl] methanol were stirred in 8 mL of dioxane under argon at 98 ° C for 16 hours. The reaction was allowed to cool and was diluted with EtOAc. The organic layers were washed with saturated NaHCO 3 and brine, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by chromatography on

155 silica gel (20% EtOAc / hexane) gave 224 mg (60%) of 6- [5-methoxy-2-hydroxymethyl-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -3- [1- (2trimetylsilanyletoxymetyl) -1H-benzimidazol-2-yl] -ΙΗ-indazole as a pale yellow oil. ^1H NMR

(300MHz, CDC1 ₃₎ δ 8.70 (d, 1 H, J = 8.4 Hz), 7.89-7.92 (m, 1H), 7.63-7.66 (M, 2H), 7.34-7.41 (m, 4H), 6, 91 (s, ih: 1, 6.29 (WITH, 2H), 5.83 (with, 2H), 5.36 (s, 2H). 4.55 (WITH, 2H), 3 78 to 3.92 (M, 5H), 3,59- 3, 70 (M, 4H), 0.83-1.04 (m, 6H) 0.03 (s, 9H), - 0, 04 (s, 9H), - 0.13 (with, 9 Hz).

Example 24 (o)

3-H-benzoimidazol-2-yl-6- (3-hydroxyphenyl) -lH-indazole

Example 24 (o) was prepared in a similar manner to that described in Example 24 (f) except that

6- (3-methoxyphenyl) -3-1H-benzimidazol-2-yl-1H-indazole prepared in a similar manner to that described in Example 24 (a) except that 3-methoxyphenylboronic acid was used instead of 5-methoxy- 2-methyl-4- [2- (trimethylsilanyl) ethoxymethoxy] phenylboronic acid in step (viii) was used in place of 6- (2-methoxy-4-hydroxyphenyl) -3-1H-benzimidazol-2-yl-indazole. ^X H NMR (300 MHz, DMSO-de) δ 13.67 (s, 1H), 13.00 (s, 1H), 9.58 (s, 1H), 8.55 (d, 1 H, J = 8 4 Hz), 7.71-7.75 (m, 2H), 7.49-7.57 (m, 2H), 7.30 (t, 1H, J = 7.8 Hz), 7.12 -7.24 (m, 4H), 6.80 (dd, 1H, J = 8.1, 1.5 Hz). MS (ES) [M + H] / z

156 calcd 327, measured 327, [M-H] / z calcd 325, measured

325th

Example 24 (p)

3-H-benzoimidazol-2-yl-6- (2-methoxy-3-hydroxyphenyl) -lH-indazole

Example 24 (p) was prepared in a similar manner to that described in Example 24 (a) except that 3-bromo-2-methoxyphenol was prepared as described by Aristoff et al., Tet. Lett., 25, 3955-58, 1984 was used in place of 4-bromo-2-methoxy-5-methylphenol in step (vi). ^X H NMR (300 MHz, DMSO-d₆) δ 13.60 (s, 1H), 12.97 (s, 1H), 9.37 (s, 1H), 8.52 (d, 1 H, J = 8 4 Hz), 7.69-7.74 (m, 2H), 7.51 (dd, 1H, J = 7.8, 1.8 Hz), 7.43 (dd, 1H, J = 8, 4.2, 1.2 Hz), 7.197.24 (m, 2H), 7.02 (t, 1H, J = 7.8 Hz), 6.85-6.93 (m, 2H),

3.50 (s, 3H). MS (ES) [M + H] / z calc. 357, measured 355, [M-H] / z calc. 357, measured 355.

Example 25 (a)

3- (3H-imidazo [4,5-c] pyridin-2-yl) -6- (4-hydroxy-2-methoxy-phenyl) -lH-indazole

157

A solution of 68 mg (0.11 mmol) of 6- [5-methoxy-2-methyl-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -3- [3- (2-trimethylsilanylethoxymethyl) -3H-imidazo [4,5c] pyridin-2-yl] -ΙΗ-indazole in 1.2 mL (1.2 mmol) of TBAF (1M in THF) with 150 mL (2.2 mmol) of ethylenediamine was stirred at 68 ° C for 48 hours. The solution was concentrated in vacuo and purified by silica gel chromatography (EtOH / EtOAc 2: 1). Precipitation from acetonitrile gave 21 mg (53%) of 3- (3H-imidazo [4,5-c] pyridin-2-yl) -6- (4-hydroxy-2-methoxyphenyl) ind-indazole as a white solid. ¹ H NMR (300 MHz, DMSO-d ₆ )? 13.70 (s, 1H), 13.49 (bs, 1H), 9.62 (s, 1H), 9.01 (bs, 1H) .

8.43 (d, 1 H, J = 8.7 Hz), 8.34 (d, 1H, J = 5.7 Hz), 7.64 1H), 7.57 (b with, 1H), 7.39 (dd, 1 H, J = 8.7, 1.5 Hz), 7.21 1H, J = 8.1 Hz) 6.55 (d, 1 H, J = 2.1 Hz), 6.49 (dd, 1 H,

8.1, 2.1 Hz), 3.74 (s, 3H). MS (ES) [m + H] / z calc 358, measured 358, [M-H] / z calc 356, measured 356.

Intermediates were prepared as follows:

(I)

1) Qs CH ₂ Cl ₂ .MeOH

IJM ^ S

3) H + CH (OMe) 9

3- (1,1-dimethoxymethyl) -6-iodo-1- (2-trimethylsilanylethoxymethyl) -1H-indazole. A solution of 1.28 g (2.69 mmol) of 6-iodo-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -4-indazole [Example 14, step (i)] in 40 mL of CH 2 Cl 2/40 mL of MeOH was stirred at -78 ° C. The reaction was treated with ozone until the blue color persisted and was then bubbled with argon. 4 ml of methylsulfide was added and the reaction was stirred for 4 hours while warming to room temperature. Concentration in vacuo gave the crude mixture

158 of acetal and aldehyde, which was converted completely to acetal by stirring in 10 ml of trimethyl orthoformate with 0.8 g of Amberlyst 15 (wet) ion exchange resin (wet) for 1 hour. The resin was removed by filtration and the solution was concentrated in vacuo. Purification by silica gel chromatography gave 1.11 g (92%) of 3- (1,1-dimethoxymethyl) -6-iodo-

1- (2-trimethylsilanylethoxymethyl) -1H-indazole as a clear oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.98 (s, 1H), 7.68 (d, 1H, J = 8.4

Hz), 7.48 (dd, 1H, J = 8.4, 1.2 Hz), 5.77 (s, 1H), 5.69 (s, 2H), 3.53 (t, 2H, J = 8.4 Hz), 3.43 (s, 6H), 0.88 (t, 2H, J =

8.4 Hz), -0.06 (s, 9H).

(Ii)

3- (1,1-dimethoxymethyl) -6- [2-methoxy-4- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] -1- (2-trimethylsilanyl-ethoxymethyl) -1Hindazol. 1.06 g (2.37 mmol) of 3- (1,1-dimethoxymethyl) -6-iodo-1- (2-trimethylsilanylethoxymethyl) -1H-indazole, 0.99 g (3.32 mmol) of 2-methoxy-4- (trimethylsilanylethoxymethoxy) Phenylboronic acid and 352 mg (1.4 mmol) of sodium carbonate were stirred in a mixture of 15 ml of benzene, 3 ml of MeOH and 1 ml of water in a flask bubbled with argon. 220 mg (0.19 mmol) of tetrakis (triphenylphosphine) palladium (0) were added and the reaction was stirred under reflux for 16 hours. The reaction was allowed to cool and was diluted with 70 mL of ether. The organic layers were washed with 30 mL H ₂ O and 30 mL brine, dried

159 (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc / hexane) gave 1.12 g (82%) of 3- (1,1-dimethoxymethyl) -6- [2-methoxy-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indazole as a pale yellow oil. ³ H NMR (300 MHz, CDCl ₃ ) δ 7.91 (d, 1H, J =

8.4 Hz), 7, 64 (with, 1H), 7.37 (dd, 1 H, J = 8, 4, 1.2 Hz), 7.29 (D, 1H, J = Q, 4 Hz) 6.71-6.77 (m, 2H), 5.82 (s, 1H), 5.75 (with, 2H), 5.28 (with, 2H), 3, 77-3,83 (m, 5H), 3.57 (t, 2H, J = 8.4 Hz), 3, 46 (with, 6H), 1.00 (t, 2H, J) = 8.4 Hz), 0.88 (t, 2 H, J =

8.4 Hz), 0.03 (s, 9H), -0.05 (s, 9H).

(Iii)

1% TFA

CHCl

6- [2-methoxy-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde. 1.1 g (1.92 mmol) of 3- (1,1-dimethoxymethyl) -6- [2-methoxy-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indole were stirred in 20 min. mL of 1% TFA and CH ₂ C1 ₂ for 1 hour at room temperature. Concentration in vacuo afforded 1.01 g (100%) of 6- [2-methoxy-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde as a clear oil, ¹ H NMR ( 3 MHz, CDC1 ₃₎ δ 10.27 (s, 1H), 8.28 (d, 1 H, J = 8.4 Hz), 7.73 (s, 1H), 7.55 (dd, 1 H, J = 8.4, 1.2 Hz), 7.29 (d, 1H, J = 8.4 Hz), 6.72-6.79 (m, 2H),

5.82 (s, 2H), 5.28 (s, 2H), 3.78-3, 84 (m, 5H), 3.61 (t, 2H, J = 8.1 Hz), 0.89 -1.03 (m, 4H), 0.03 (s, 9H), -0.05 (s, 9H).

(Iv)

160

6- [5-methoxy-2-methyl-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -3- [3- (2-trimethylsilanylethoxymethyl) -3H-imidazo [4,5-c] pyridin-2-yl] -ΙΗ-indazole. 320 mg (0.61 mmol) of 6- [2-methoxy-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde, 68 mg (0.62 mmol) 3.4 -diaminopyridine and 23 mg (0.73 mmol) of sulfur were taken up in 2 mL of dry DMF and stirred at 90 ° C for 16 hours under an argon atmosphere. The reaction was allowed to cool and was diluted with 20 mL EtOAc. The organic layers were washed with saturated NaHCO ₃ and brine, 15 mL each, dried (Na 2 SO 4 and concentrated in vacuo. Purification by silica gel chromatography (75% to 100% EtOAc / hexane) gave 78 mg (21%) of 6- [5-methoxy -2-methyl-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -3- [3- (2-trimethylsilanylethoxymethyl) -3H-imidazo [4,5-

c] pyridin-2-yl] -1H-indazole as a white solid. ^X H NMR (300 MHz, CDC1 ₃₎ δ 10.69 (br s, 1H), 9.21 (s, 1H), 8.63 (dd, 1 H, J = 8.4, 0.3 Hz); 8.50 (d, 1H, J = 5.4 Hz), 7.73 (s, 1H), 7.47 (bs, 1H), 7.57 (dd, 1H, J = 8.7.1) 2 Hz), 7.33 (d, 1H, J = 8.4 Hz), 6.74-6, 80 (m, 2H), 5.80 (s, 2H), 5.29 (s, 2H) ), 3.78-3.85 (m, 5H), 3.63 (t, 2H, J = 8.1 Hz), 0.89-1.04 (m, 4H), 0.04 (s, 9H), -0.06 (s, 9H).

Example 25 (b)

3- [6- (2-Morpholin-4-ylethylcarbamoyl) -1H-benzimidazol-2-yl] -6- (2-methoxy-4-hydroxyphenyl) -1H-indazole

161

The compound of Example 25 (b) was prepared in a similar manner to that described in Example 25 (a) except that 3,4-diamino-N- (2-morpholin-4-ylethyl) benzamide was prepared as described below, was used instead of 3,4-diaminopyridine in step (iv). Ή NMR (300 MHz, DMSO-d ₆ ) δ 13.61 (s, 0.5H),

13.59 (s, 0.5H), 13.22 (s, 0.5H), 13.18 (s, 0.5H), 9.59 (s,

1H), 8, 35-8, 46 (m, 2H), 8.27 (s, 0.5H), 8.02 (s, 0.5H), 7.71-

7.79 (m, 1.5H), 7.63 (s, 1H) 7.53 (D, 0.5H, J = 8.7 Hz), 7.38 (D, 1 H, J = 8.7 Hz), 7.21 (d, 1 H, J = 8.7 Hz), m.p. 5.55 (d, 1 H, J) = 2, 1 Hz), 6.49 (dd, 1H, J = 8.4, 2.1 Hz), 3.75 (s, 3H), 3.58 (T, 4H, J = 4.5Hz) 3.42 (q, 2 H, J = = 6.0 Hz), 2.43-2.51 (m, 6H). MS (ES) [M + H] / z ; calculated 513. measured 513, [m-H] / z

calculated 511, measured 511.

3,4-Diamino-N- (2-morpholin-4-ylethyl) benzamide was prepared as follows:

BX ^ AEA D »** P, tw

3,4-diamino-N- (2-morpholin-4-yl-ethyl) -benzamide. 5 g (32.9 mmol) of 3,4-diaminobenzoic acid, 5.2 ml (39.4 mmol) of 4- (2-aminoethyl) morpholine, 9.2 ml (66 mmol) of triethylamine and DMAP 0.40 g (3, 3 mmol) was added to 80 mL dry DMF at 0 ° C. 9.45 g (49.3 mmol) EDC was added and the reaction was stirred for 24 hours at room temperature. Concentration in vacuo and purification by silica gel chromatography (10% MeOH / CH ₂ Cl ₂ with 0.2% NH ₄ OH) gave 2.6 g

162 (31%) 3,4-diamino-N- (2-morpholin-4-ylethyl) benzamide as a light brown solid. 1 H NMR (300 MHz, DMSO-d 6) δ 7.72 (t, 1H, J = 5.4 Hz), 7.02 (d, 1H, J = 1.8 Hz), 6.92 (dd, 1H, J = 8.1,

1.8 Hz), 6.46 (d, 1H, J = 8.1 Hz), 4.89 (bs, 2H), 4.51 (bs, 2H), 3.55 (t, 4H, J = 4.8 Hz), 3.29 (q, 2H, J = 7.2 Hz), 2.362, 43 (m, 6H).

Example 25 (c)

3- [6- (4-methylpiperazin-l-yl) -lH-benzimidazol-2-yl] -6- (2-methoxy-4-hydroxyphenyl) -lH-indazole

OH

The compound of Example 25 (c) was prepared in a similar manner to that described in Example 25 (a) except that

4- (4-methylpiperazin-1-yl) benzene-1,2-diamine (Harapanhalli et al., J. Med. Chem., 39, 4804-09, 1996) was used in place of

3,4-diaminopyridine in step (iv). NMR (300 MHz, DMSO-d6) δ

13.51 (s, 0.33H), 13.38 (s, 0.67H), 12.66 (s, 0.33H), 12.59 (s, 0.67H), 9.58 (s, 1H), 8.42 (d, 0.33H, J = 8.4 Hz), 8.41 (d, 0.67H, J = 8.4 Hz), 7.59 (s, 1H), 7, 55 (d, 0.67H, J = 8.7)

Hz), 7.31-7.37 (m, 1.33H), 7.20 (approximately d, 1.33H, J = 8.4

Hz), 6.92-7.01 (m, 1.67H), 6.55 (d, 1H, J = 1.5 Hz), 6.48 (dd,

1H, J = 8.4, 2.1 Hz), 3.74 (s, 3H), 3.12 (bs, 4H), 2.50 (bs,

4H), 2.22 (s, 3H). MS (ES) [M + H] / z calc. 455, measured

455, [M-H] / z calcd 453, measured 453.

Example 25 (d)

3- [4- (4-methylpiperazin-1-yl) -1H-benzimidazol-2-yl] -6- (2-methoxy-4-hydroxyphenyl) -1H-indazole

163

Example 25 (d) was prepared in a similar manner to that described in Example 25 (a) except that 3- (4-methylpiperazin-1-yl) benzene-1,2-diamine (Harapanhalli et al., J. Med. Chem., 39, 4804-09, 1996), analogous to the 4-isomer, was used in place of 3,4-diaminopyridine in step (iv). ^X H NMR (300 MHz, DMSO-de) δ 13.41 (br s, 1H), 12.79 (br s, 1 H), 9.60 (br s, 1H), 8.37 (d, 1 H, J = 8.4 Hz), 7.60 (s, 1H),

7.36 (dd, 1H, J = 8.4, 1.2 Hz), 7.22 (d, 1H, J = 8.4 Hz),

7. 03-7.07 (m, 2H), 6.46-6.56 (m, 3H), 3.75 (s, 3H), 3.62 (bs,

4H), 2.62 (bs, 4H), 2.28 (s, 3H). MS (ES) [M + H] / z calcd

455, measured 455, [M-H] / z calcd 453, measured 453.

Example 25 (e)

3-imidazol-2-yl-6- (2-methoxy-4-hydroxyphenyl) -lH-indazole

The compound of Example 25 (e) was prepared in a similar manner to that described in Example 25 (a) except that 6- [5-methoxy-2-methyl-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1 (2) was prepared. -trimethylsilanylethoxymethyl) -3-imidazol-2-yl-1H-indazole was used in place of 6- [5-methoxy-2-methyl-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1- (2-trimethylsilanylethoxymethyl) -3 [3] - (2-trimethylsilanyl-ethoxymethyl) -3 H -imidazo [4,5- c] pyridin-2164

yl] -lH-indazole . ^ς Η NMR (300 MHz DMSO-d?) δ 13,10 (with, 1H), 12.59 (s, 1 H), 9.56 (s, 1H), 8.27 (d, 1 H, J = 8.4 Hz), 7, 53 (s, 1H), 7.25 (dd, 1 H, J = 8 , 4, 1 , 2 Hz) 7.13-7.20 (M, 3H); 6.54 (d, 1 H, J) = 2.1 Hz) , 6.47 (Dd, 1 H, J = 8.4, 2.1 Hz); 3.73

(s, 3 H). MS (ES) [M + H] / z calc. 307, measured 307.

The starting material was prepared as follows:

0.4 ml (3.5 mmol) of 40% (by weight) glyoxal in H ₂ O was added dropwise to a solution of 420 mg (0.8 mmol) of 6- [2-methoxy-4- (2-trimethylsilanyl-ethoxymethoxy) -phenyl] - 1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde, from Example 25 (a) step (iii) and 0.6 ml of 28% aqueous ammonia in 8 ml THF / 8 ml MeOH, and the solution was stirred at room temperature for 16 hours. The reaction was concentrated in vacuo and dissolved in 50 mL of CHCl ₃ . The organic layers were washed with Η ₂ Ο and brine, 25 mL each, dried (Na ₂ SO ₄ ) and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc / hexane) gave 120 mg (27%) of 6- [5-methoxy-2-methyl-4- (2-trimethylsilanylethoxymethoxy) phenyl] -1 (2-trimethylsilanylethoxymethyl) -3-imidazole -2-yl-1H-indazole as a clear oil. ^X H NMR (300 MHz, CDC1 ₃₎ δ 10.03 (s, 1H), 8.48 (d,

1H, J = 8.4Hz), 7.65 (s, 1H), 7.46 (dd, 1H, J = 8.4, 1.5Hz),

7.29-7.48 (m, 2H), 7.13 (d, 1H, J = 1.5 Hz), 6.73-6.78 (m,

2H), 5.73 (s, 2H), 5.28 (s, 2H), 3.78-3.86 (m, 5H), 3.60 (t,

2H, J = 8.4 Hz), 0.88-1.03 (m, 4H), 0.03 (s, 9H), -0.05 (s,

9H).

Example 25 (f)

165

3- [4- (2-hydroxyethylsulfanyl) -lH-benzoimidazol-2-yl] -6- (2-methoxy-4-hydroxyphenyl) -ΙΗ-indazole

The compound of Example 25 (f) was prepared in a similar manner to that described in Example 25 (a) except that

2- (2,3-diaminophenylsulfanyl) ethanol was used instead of 3,4-diaminopyridine in step (iv). ¹ H NMR (300 MHz, DMSO-d 6) δ 13.51 (s, 1H), 13.02 (s, 1H), 9.59 (s, 1H), 8.45 (d, 1H, J = 8) 4

Hz), 7.61 (s, 1H), 7.32-7, 40 (m, 2H), 7.11-7.23 (m, 3H), 6.55

(d, 1 H, J = 2.4 Hz), 6.48 (dd, 1H, J = 8.1, 2.4 Hz), 4.96 (b s, 1H) 3.75 (s, 3H), 3.65 (bs, 2H), 3.33 (t, 2H, J = 6.9 Hz). MS (ES) [m + Na] / z calculated 455, measured 455, [M-H] / z

calculated 431, measured 431.

The starting material was prepared as follows:

KjCQ.DMF

BOA:

2- (3-amino-2-nitro-phenylsulfanyl) -ethanol. 1.12 g (6.5 mmol)

Of 3-chloro-2-nitroaniline, 0.60 mL (8.6 mmol) of 2-mercaptoethanol and 0.99 g (7.1 mmol) of potassium carbonate were placed in 15 mL of dry DMF and stirred at 130 ° C for 4 hours. hours. The solution was allowed to cool and was concentrated in vacuo. Purification by silica gel chromatography (70% EtOAc / hexane) gave 1.29 g (93%) of 2- (3-amino-2-nitrophenylsulfanyl) ethanol as a bright red solid. ^{@ 1} H NMR (300 MHz, DMSO-d6) _.delta

7.20 (t, 1H, J = 8.1 Hz), 6.80 (s, 2H), 6.73 (dd, 1H, J = 8.4,

166

0.9 Hz), 6.63 (dd, 1H, J = 7.8, 1.2 Hz), 4.92 (t, 1H, J = 6.0 Hz), 3.58 (q, 2H, J = 6.0 Hz), 2.98 (t, 2H, J = 6.0 Hz).

2- (2,3-diaminofenylsulfanyl) ethanol. 1.02 g (4.8 mmol)

2- (3-amino-2-nitrophenylsulfanyl) ethanol was reduced by hydrogenation using 45 psi H ₂ with 180 mg of 10% Pd / C in 25 mL of EtOAc for 6 hours. After filtration through celite, the solvent was removed in vacuo. Purification by silica gel chromatography (EtOAc) afforded 762 mg (87%)

2- (2,3-diaminophenylsulfanyl) ethanol as a light yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 6.98 (dd, 1H, J = 7.5, 1.5 Hz), 6.66-6.72 (m, 2H), 3.65 (t, 2H, J = 5.7 Hz), 3.55 (bs, 5H), 2.91 (t, 2H, J = 5.7 Hz).

Example 25 (g)

3- (5-methylcarbamoyl-lH-benzoimidazol-2-yl) -6- (2-methoxy-4-hydroxyphenyl) -lH-indazole

Example 25 (g) was prepared in a similar manner to that described in Example 25 (a) except that

3,4-diamino-N-methylbenzamide (Kumar, et. Al. J. Med. Chem., 27, 1083-89 1984) was used in place of 3,4-diaminopyridine in step (iv). ¹ H NMR (300 MHz, DMSO-d 6) δ 13.59 (s, 0.5H), 13.55 (s,

0.5H), 13.21 (s, 0.5H), 13.14 (s, 0.5H), 9.60 (s, 1H), 8.389.46 (m, 2H), 8.26 (s 0.5H), 8.03 (s, 0.5H), 7.71-7.79 (m,

1.5H), 7.63 (s, 1H), 7.52 (d, 0.5H, J = 8.4 Hz), 7.35-7.40 (m, 1H), 7.21 (d 1 H, J = 2.1 Hz), 6.55 (d, 1H, J = 2.4 Hz), 6.49 (dd, 1H, J = 8.4, 2.4 Hz), 3.75 (s, 3H), 2.82 (d, 1.5H, J =

167

0.5 Hz), 2.81 (d, 1.5H, J = 1.5 Hz). MS (ES) [M + H] / z calcd 414, found 414, [M-H] / z calcd 412, measured 412.

Example 25 (h)

3- (5-dimethylamino-lH-benzoimidazol-2-yl) -6- (2-methoxy-4-hydroxyphenyl) -lH-indazole

The compound of Example 25 (h) was prepared in a similar manner to that described in Example 25 (a) except that

3,4-diamino-N, N-dimethylaniline (Cazaux, et. Al., Can. J. Chem., 71, 1236-46 1993) was used instead of 3,4-diaminopyridine in step (iv). ⁷ H NMR (300 MHz, DMSO-d 6) δ 13.36 (s, 1H), 12.51 (bs, 1, 9.58 (s, 1H), 8.42 (d, 1H, J = 8) (Hz, 4 Hz), 7.59 (s, 1H),

7.49 (b, 1H), 7.33 (dd, 1 H, J = 8.4, 1.2 Hz), 7.20 (d, 1H, J) = 8.1 Hz), 6, 87 (br d, 2H, J) = 8.1 Hz! 1.65 (d, 1H, J = 2.1) Hz), 6.48 (Dd, 1H, J = 8.1, 2.1 Hz), 3.73 (s, 3H), 2.92 (s,

6H). MS (ES) [M + H] / z calc 400, measured 400, [M-H] / z calc 398, measured 398.

Example 25 (i)

3- (5-aminosulfonyl-lH-benzoimidazol-2-yl) -6- (2-methoxy-4-hydroxyphenyl) -lH-indazole

168

Example compound prepared in a manner similar to that described in the Example

25 (a), except that 3,4-diamino-3,4-diaminobenzenesulfonamide has been used

pyridine in step (iv). ¹ H NMR (300 MHz, DMSO-d 6) 0.5H), 13 ;, 64 (s, 0.5H), 13 39 (s, 0.5H), 13, 35 (p (with, 1H), 8.43 (d, 1H, J = 8.1 Hz), 8.18 (d, 0, 5H, 7, 99 (D, 0.5H, J = 1/5 Hz] 1, 7.86 (d, 0.5H, J = 8 7.72 (M, 2.5 Hz), 7, 29 (D, 1H, J = 8.4Hz), 7,20- 6.55 (D, 1 H, J = 2.1 Hz ) 6.49 (dd, IH, J = 8.4. (with, 3H). MS (ES) [M + H] / z calcd 436, measured

measured 434.

δ 13.67 (s,

7.28 (m,

2.1 Hz), 4 Hz), 0.5H), 9.60

436, [M-H] / z calcd 434,

3.75

Example 25 (j)

3- (4-Methylcarbamoyl-1H-benzimidazol-2-yl) -6- (2-methoxy-4-hydroxyphenyl) -1H-indazole

Example 25 (i) was prepared in a similar manner to that described in Example 25 (a), 2,3-diamino-N-methylbenzamide was used instead of 3,4-diaminopyridine in step (iv). ^X H NMR (300 MHz, DMSO-de) δ 13.71 (s, 1H), 13.46 (s, 1 H), 9.85 (br d, 1H, J = 4.8 Hz), 9.61 (s, 1H), 8.38 (d, 1H, J = 8.4 Hz), 7.89 (dd, 1H, J = 7.5, 1.2 Hz), 7.66-7.72 ( m.

169

2H), 7.47 (dd, 1H, J = 8.4, 1.2) Hz); 7.36 (t, 1 H, J = 7.8 Hz), 7.23 (d, 1H, J = 8.1 Hz), 6.56 (D, 1H, J = 2.4Hz) 6, 50 (Dd, 1H, J = 8.4, 2.4 Hz), 3.76 (s, 3H), 3.10 (d, 3 H, J = 1.8 Hz). MS (ES) [m + H] / z calcd 414. measured 414, [M- H] / z calcd 412, measured 412. 2,3-diamino-N-methylbenzamide he was prepared as follows:

2-Amino-N-methyl-3-nitro-benzamide.

1.8 g (9.9 mmol)

2-amino-3-nitrobenzoic acid a

1.33 g (19.8 mmol) of methylamine hydrochloride was stirred in 30 mL of dry CH 2 Cl 2/5 mL of DMF at 0 ° C.

2.83 g (14.8 mmol) of EDC a were added

4.92 ml (27.7 mmol) of DIEA and the solution was stirred for 3 hours while warming to room temperature. The reaction was concentrated in vacuo and purified by silica gel chromatography (8% mixture)

MeOH a CHCl3) for to give 1,42 g (74%) 2-Amino-N-methyl-3- nitrobenzamide than yellow solid substances. NMR (300 MHz, DMSO-d?) δ 8.58 (with s, 1F, 8.23 (b s, 2H), 8.15 (dd, 1 H, J = 8.1, 1.8 Hz), 7 82 (dd, 1 H, J = 8.1 , 1.8 Hz) 6.68 (t, 1H, J =

8.1 Hz), 2.76 (d, 3H, J = 4.5 Hz).

2,3-diamino-N-methylbenzamide. 1.4 g (7.2 mmol) of 2-amino-N-methyl-3-nitrobenzamide was reduced by hydrogenation using 50 psi of H ₂ with 250 mg of 10% Pd-C in 25 mL of EtOAc for 5 hours. After filtration through celite, the solvent was removed in vacuo. Purification by silica gel chromatography (10% MeOH / CHCl ₃ ) gave 1.08 mg (91%) of 2,3-diamino-

N-methylbenzamide as a light yellow solid. NMR (300 MHz, CDCl 3) δ 6.87 (dd, 1H, J = 7.8, 1.5 Hz), 6.76 (dd, 1H, J = 7.8,

1.5 Hz), 6.59 (t, 1H, J = 7.8 Hz), 6.14 (bs, 1H), 4.28 (bs, 4H), 2.95 (d, 3H, J = 5.1 Hz).

170

Example 26

6- (4-hydroxy-3-methoxyphenyl) -3- [E-2- (4-glycylaminophenyl) ethenyl] -1H-indazole

The compound of Example 26 was prepared from the starting material described below in a similar manner to that described for Example 1 (a): ^R H NMR (300 MHz, CDC1 ₃₎ δ 8.29 (d, 1H), 7.80 (m, 5H), 7.58 (m, 3H), 7.38 (s, H), 7.27 (d, 1H), 7.01 (d, 1H), 4.00 (s, 3H), 3, 42 (s, 2H), LCMS (100% area) R t = 3.44 minutes (pos) [M + H] / z calcd 415.1, measured 415.2.

The starting material was prepared as follows:

(I)

3-Iodo-6- {3-methoxy-4-methoxymethoxyphenyl) -1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole was prepared from the compound prepared in Example 1 (a), step (v), in a similar manner, as described for Example 10, step (ii): R f sm 0.11, p 0.43 (ethyl acetate: hexane 3: ^7); H NMR (300 MHz, CDCl3) δ 7.71 (s, 1H) 7.55 (m, 2H), 7.33 (m, 1H), 7.20 (m, 2H), 5.82 (s, 2H), 5.33 (s, 2H), 4.02 ( s, 3H), 3.64 (t, 2H), 3.59 (s, 3H), 0.95 (t, 2H), .03 (s, 9H).

(Ii)

171

3-Styryl-6- (3-methoxy-4-methoxymethoxyphenyl) -1- [2- (trimethylsilanyl) ethoxymethyl] -4-indazole was prepared in a similar manner to that described in Example 11, step (iii): R f sm 0 , 41, p 0.35 (2: 8 ethyl acetate / hexane), NMR (300 MHz,

CDCl ₃ ) δ 8.12 (d, 1H) 7.73 (S, 1H), 7.62 (M, 2H), 7.51 (m, 2H) hours), 7.46 (m, 2H) 7.38 (M, 1H), 7.30 (M, 4H), 5.85 (s, 2H), 5.38 (s, 2H), 4.03 (s, 3H) 3.70 (t, 2H) r 3.62 (s, 3H) 0.98 (t, 2H). -0.02 (s, 9H).

3-Carboxaldehyde-6- (3-methoxy-4-methoxymethoxyphenyl) -1- [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole was prepared

like way than It was disclosed in Example 33 (a) step (i): ^X H NMR (300 MHz, CDCl3) δ 10,33 (s, 1 H), 8.34 (D, 1H), 7.82 (s, 1H), 7.65 (D, 1H), 7.25 (m, 3H), 5.90 (with, 2H), 5.36 (s, 2H) 4.02 (s, 3H); 3, 67 (t, 2H) 3.51 (s, 3H), 0, 98 (T,

2H), -0.02 (s, 9H).

(Iv)

172

3- (4-nitrostyryl) -6- (3-methoxy-4-methoxymethoxyphenyl) -1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole was prepared in a similar manner to that described in Example 33 (a), step (ii) except that 4-nitrobenzyltriphenylphosphonium bromide and lithium hexamethyldisilazide were used instead

2-picolyltriphenylphosphonium chloride / potassium hydride: LCMS (100% area) Rt = 6.89 min (pos) [M + H] / z calcd

562.4, measured 562.4.

(in)

3- (4-nitrostyryl) -6- (3-methoxy-4-methoxymethoxyphenyl) -1H-indazole was prepared in a similar manner to that described in Example 11: FTIR (thin film) 3335, 3178, 2954, 1592, 1512, 1338, 1257, 1136, 1257, 1136, 987 cm ^{-1, Χ Η} NMR (300 MHz, CDC1 ₃₎ δ 8.22 (d, 2H, J = 8.8 Hz), 8.02 (d, 1 H, J = 8.5 Hz), 7.70 (d, 2H, J = 8.8 Hz), 7.58 (m, 3H), 7.45 (dd, 1H, J = 1.3, 8.5 Hz) .

7.20 (m, 4H), 7.26 (s, 2H), 3.95 (s, 3H), 3.53 (s, 3H), LCMS (100% area) Rt = 5.13 minutes (pos. ) [M + H] / z calc. 432.1, measured 432.1.

(Vi)

173

3- (4-aminostyryl) -6- (3-methoxy-4-methoxymethoxyphenyl) -1Hindazole was prepared in a similar manner to that described in Example 11, step (iv): R f sm 0.39, p 0.26 (mixture ethyl acetate and hexane 6: 4), FTIR (thin film) 3366, 3210, 2954, 1608, 1517, 1465, 1412, 1259, 1157, 1077, 989, 912 cm ^-1 , ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.11 (d, 1H), 7.63 (s, 1H), 7.50-7.15 (m, 8H), 6.71 (d, 2H), 5.36 (s, 2H), 3 97 (s, 3H), 3.61 (s, 3H), LCMS (100% region) Rt = 4.40 min (pos) [M + H] / z calcd 402.2, measured 402.2.

(Vii)

mg (0.224 mmol) of 3- (4-aminostyryl) -6- (3-methoxy-4-methoxymethoxyphenyl) -1H-indazole was dissolved in 2 mL of dichloromethane and treated with 196 mg (1.12 mmol, 5 eq) Bocglycine, 82 mg (3 eq) DMAP and 426 mg (5 eq) HATU. The mixture was left under stirring for 30 minutes. The mixture was partitioned between ethyl acetate and water. The organic was concentrated, taken up in 5 mL of methanol and treated with 100 mg of potassium carbonate. The mixture was heated to 50 ° C for 3 days. The resulting mixture was again partitioned between ethyl acetate and water. The organic material was concentrated and purified on silica gel, 109 mg (66%): R f sm 0.32, p 0.46 (ethyl acetate-hexane 6: 4), ^X H NMR (300 MHz, CDC1 ₃₎ δ 8.18 (bs, 1H), 8.03

174 (d, 1H, J = 8.1Hz), 7.56 (m,

5.29 (s, 2H), 5.20 (bs, 1H), (s, 3H), 1.48 (s, 9H).

5H), 7.40 (m, 3H), 7.20 (m, 3H)

3.98 (s, 3H), 3.96 (d, 2H), 3.54

Example 27 (a)

6-phenyl-3-E-styryl-lH-indazole

345 mg (0.81 mmol) of 6-phenyl-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole was treated with a 16 mL (16 mmol) solution of TBAF, an IM solution in THF, and 0, 53 ml (8.1 mmol) of ethylenediamine and heated at 70 ° C for 2 hours. The solution was then poured into 200 ml of brine and extracted with 3 x 30 ml of ethyl acetate. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. Purification by silica gel chromatography gave 80 mg (34%) of 6-phenyl-3-E-styryl-1Hindazole as a white solid: ¹ H NMR (300 MHz, CDCl 3) δ

8.10 (d, 1H, J = 8.5 Hz), HRMS (FAB) [M + H] / z calcd 297.1392, found 297.1393. Anal, Calc'd: C (85.10), H (5.44), N (9.45) .Namer: C (85.10), H (5.46), N (9.43).

The starting material was prepared as follows:

(I)

Solution 476 mg

(1.0 mmol)

6-iodo-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -4-indazole, from Example 14, step (i), in 3

175 ml dioxane (degassed by sonication and argon bubbling), 23 mg (0.05 mmol) Pd (PPh ₃ ) ₄ , 302 mg (2.5 mmol) phenylboronic acid and 1.25 ml 2M aqueous Na ₂ CO ₃ (degassed) as above) was heated at 90 ° C for 2 hours. The solution was then diluted with 100 mL ethyl acetate and washed with 2 x 20 mL brine. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. Purification by silica gel chromatography gave 345 mg (81%) of 6-phenyl-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole as a brown oil. ^X H NMR (300 MHz, CDC1 ₃₎ δ 8.09 (d, IH, J = 8.5, 0.7 Hz), 7.75 (s, IH), 7.70 (d, IH, J = 7.0 Hz), 7.64-7.58 (m, 2H), 7.56-7.51 (m, 2H), 7.50-7.45 (m, 2H), 7.45-7 36 (m, 4H), 7.34-7.27 (m, 1H), 5.80 (s, 2H), 3.73 (t, 2H, J = 8.3 Hz), 1.12 ( t, 2H, J =

8.3 Hz).

Example 27 (b)

6- (3-methoxyphenyl) -3-E-styryl-lH-indazole

The compound of Example 27 (b) was prepared in a similar manner to that described in Example 27 (a) except that 3-methoxyphenylboronic acid was used in place of phenylboronic acid in step (i). ^X H NMR (300 MHz, MeOH-d ₄₎ δ

8.16 (d, 1H, J = 8.4 Hz), 7.70 (s, 1H), 7.67-7.61 (m, 2H), 7.60-7.43 (m, 3H) 7.43-7.33 (m, 3H), 7.32-7.21 (m, 3H), 6.99-

6.92 (m, 1H); 3.88 (s, 3H). HRMS (FAB) [M + Na] / z calcd

349.1317, measured 349.1342. Analyzed with 0.1 H ₂ O, calculated: C (80, 50), H (5.59), N (8.55) .Namer: C (80, 44.), H (5.49), N (8.55).

6- (4-methoxyphenyl) -3-E-styryl-1H-indazole

176

Example 27 (c)

The compound of Example 27 (b) was prepared in a similar manner to that described in Example 27 (a) except that

4-methoxyphenylboronic acid was used in place of phenylboronic acid in step (i). ^{Χ Η} NMR (300 MHz, _DMSO-d6) d 13.20 (s, IH), 8.23 (d, IH, J = 8.4 Hz), 7.76 to 7, 64 (m, 5H) 7.54 (s, 1H); 7.50-7.37 (m, 3H); 7.33-7.25 (m, 1H);

2H, J = 8.8 Hz), 3.82 (s, 3H) HRMS (FAB) [M + H] / z calcd

327.1497, measured 327.1502. Anal. Calc'd: C (80.96), H (5.56), N (8.58). Found: C (80.71), H (5.42), N (8.47).

Example 27 (d)

6-naphth-l-yl-3-E-styryl-lH-indazole

The compound of Example 27 as described in U.S. Pat

Phenylboronic acid 1-naphthaleneboronic acid in step δ 10.11 (s, 1H), 8.45 (d, IH,

7.66-7.37 (m, 13H), 7.35-7.28 calculated 369.1368, measured (d) was prepared similar to Example 27 (a) except that it was used instead of (i). ¹ H NMR (300 MHz, DMSO- _d) J = 8.41), 7. 97 to 7.87 (m, 3H), (m, IH). HRMS (FAB) [M + Na] / z

369.1359. Anal. Calculation: C

177 (86, 68), [delta] (5.32), N (8.19). Found: C (86.52), H (5.32), N (8.19).

Example 27 (e)

6-pyridin-3-yl-3-E-styryl-lH-indazole

she was

Example compound

prepared by a similar example was (a) except that the acid used was as described in U.S. Pat

3-pyridineboronic

phenylboronic of acid in step (i). NMR (300 MHz, δ 8.97 (s, 1 H) 8.63 (d, 1H, J = = 4.8 Hz) 8.30 (d, 1 H, Hz), 8.27 (d, 1H, J = 8.1Hz), 7.86 (with, 1H), 7.72 (d,

MeOH-d)

H

2H, J

7.5

8.5

754-7, 42 (m, 2 H), 7, 40-7, 32 (m,

HRMS (FAB) [M + H] / z calc. 298.1344, found

298.1356. Analyzed with 0.25

_H2O Calc'd, C (79.58), H

Example 27 (f)

6-pyridin-4-yl-3-E-styryl-lH-indazole

The compound of Example 27 (f) was prepared in a similar manner to that described in Example 27 (a) except that

4-pyridineboronic acid was used instead of phenylboronic acid in step (i) ¹ H NMR (300 MHz, MeOH-dJ)

178 δ 8.69 (bs, 2H), 8.30 (d, 1H, J = 8.5 Hz), 7.96 (s, 1H), 7.87 (d, 2H, H = 5.6) Hz), 75-7.68 (m, 3H), 7.68-7, 50 (m, 2H),

7.50-7.42 (m, 2H); 7.40-7.31 (m, 1H). HRMS (FAB) [M + H] / z calc. 298.1344, found 298.1357. Analyzed with 0.3 H ₂ O, calculated: C (79.34), H (5.19), N (13.88). Found: C (79.14), H (5.08), N (13.84).

Example 27 (g)

6-indol-4-yl-3-E-styryl-lH-indazole

The compound of Example 27 (g) was prepared in a similar manner to that described in Example 27 (a) except that

4-Indolboronic acid was used in place of phenylboronic acid in step (i). ¹ H NMR (300 MHz, MeOH-d ₄ ) δ 8.25 (d, 1H, J = 8.5 Hz), 7.85 (s, 1H), 7.75-7.67 (m, 3H) 7.67-7.52 (m, 2H), 7.52-7.42 (m, 3H), 7.39-7.22 (m, 4H), 6.72 (d, 1H, J =

3.2 Hz). HRMS (FAB) [M + H] / z calc. 336.1501, found 336.1506. Analyzed with 0.3 H ₂ O, calculated: C (78.97), H (5.36), N (12.01). Found: C (78.95), H (5.20), N (12.03).

Example 27 (h)

6- [3-ethoxy-4-hydroxyphenyl] -3-E-styryl-lH-indazole

179

The compound of Example 27 (h) was prepared in a similar manner to that described in Example 27 (a) except that 3-ethoxy-4- (2-trimethylsilanylethoxymethoxy) benzeneboronic acid was used in place of phenylboronic acid in step (i). ³ H NMR (300 MHz, CDCl ₃ ) δ 8.10 (d, 1H, J = 8.7 Hz), 7.74 (s, 1H), 7.74-7.16 (m, 10H), 7 07 (d, 1H, J = 8.15 Hz), 4.27 (q, 2H, J = 14.0 Hz), 1.54 (t, 3H, J = 14.0 Hz). HRMS (FAB) [M + H] / z calc. 357.1603, found 357.1611. Analyzed with 0.2 H ₂ O, calculated: C (76.73), H (5.71), N (7.78). Found: C (76.72), H (5.91), N (7.43).

The starting material was prepared as follows:

(I)

4-Bromo-2-ethoxy-phenol (Smith et al., Soc. PI, 1877-78, 1992) was converted to 3-ethoxy-4- (2-trimethylsilanylethoxymethoxy) benzeneboronic acid in a manner similar to that described in Example 24 (a) steps (vi) - (vii). ¹ H NMR (300 MHz, (CDCl 3) δ 7.82 (d, 1H, J = 8.0 Hz), 7.72 (s, 1H), 7.31 (d,

1H, J = 8.1 Hz), 5.37 (s, 2H), 4.29 (q, 2H, J = 14.0 Hz), 3.87 (t, 2H, J = 16.8 Hz) 1.54 (t, 2H, J = 14.0 Hz); 0.99 (t, 2H,

J = 16.8 Hz), 0.03 (s, 9H).

180

Example 27 (i)

6- [3- (2-hydroxyethoxy) -4-hydroxyphenyl] -3-E-styryl-lH-indazole

The compound of Example 27 (i) was prepared in a similar manner to that described in Example 27 (a) except that

3- [2- (trimethylsilanylethoxymethoxy) ethoxy) -4- (2-trimethylsilanylethoxymethoxy) benzeneboronic acid prepared from 2- (2-hydroxyethoxy) phenol (Yamaguchi et al., Bull. Chem. Soc. Jpn., 61, 2047-54, 1988) in a similar manner to that described in Example 24 (c), by steps (i) - (iii), was used instead of phenylboronic acid in step (i). ^X H NMR (300 MHz, _LMSO-d6) δ 8.17 (d, 1 H, J = 8.7 Hz), 7.73 to 7.17 (m, 11 H), 6.92 (d, 1 H, J = 8.2 Hz), 4.13 (t, 2H, J = 9.7 Hz), 3.8 (t, 2H, J = 9.7 Hz). HRMS (FAB) [M + H] / z calc. 373.1552, found 373.1563. Analyzed with 0.05 trifluoroacetic acid, calculated: C (73.37), H (5.35), N (7.41). Found: C (73.11), H (5.33), N (7.39).

Example 27 (j)

6- (3,4-dimethoxyphenyl) -3-E-styryl-lH-indazole

The compound of Example 27 (j) was prepared in a similar manner to that described in Example 27 (a) except that

3,4-dimethoxyphenylboronic acid was used instead

181 of the phenylboronic acid in step (i). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.01 (d, 1H, J = 8.1 Hz), 7.51-7.05 (m, 11H), 6.86 (d, 1H) J = 8.0 Hz), 3.58 (s, 3H), 3.65 (s, 3H). HRMS (FAB) [M + H] / z calc. 357.1598, found 357.1508. Analyzed with 0.2 H ₂ O, calculated: C (76.73), H (5.71), N (7.78). Found: C (76.45), H (5.70), N (7.68).

Example 27 (k)

6- (2-methoxypyridin-5-yl) -3-E-styryl-lH-indazole

OMe

6- (2-Methoxy-pyridin-5-yl) -3 - ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazole was converted to 6- (2-methoxy-pyridin-5-yl) -3-E -styryl-1H-indazole in a manner similar to that described in Example 27 (a). ^X H NMR (300 MHz, CDC1 ₃₎ δ

8.53 (d, 1H, J = 2.1 Hz), 8.15 (d, 1H, J = 9.2 Hz), 7.97 (dd, 1H, J = 2.6, 8.6 Hz) 7.79 (s, 1H), 7.74-7.34 (m, 8H), 6.94 (d, 1H, J = 8.6 Hz). HRMS (FAB) [M + H] / z calc. 328.1450, found 328.1462. Anal. Calcd. C (77.04), H (5.23), N (12.83). Found: C (77.00), H (5.28), N (12.65).

The starting material was prepared as follows:

(I)

A solution of 2.00 g (6.10 mmol) of 5-bromo-2-methoxy-pyridine, 1.15 g (6.10 mmol) of hexamethyldicin and 0.28 g (0.24 mmol) of Pd (PPh ₃ ) ₄ in 10

182 ml of degassed dioxane was heated to reflux for 16 hours. 2.90 g (6.10 mmol) of 6-iodo-3 ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazole was added to the above mixture, followed by 0.35 g (0.31 mmol) ) of Pd _{(PPh3) 4th} The reaction mixture was heated to reflux for 16 hours. The mixture was then diluted with 150 mL of ethyl acetate and washed with 30 mL of brine. The organic layers were dried over MgSO ₄ , and then concentrated under reduced pressure. Purification by silica gel chromatography gave 1.12 g (40%) of 6- (2-methoxy-pyridin-5-yl) -3 - ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazole as a yellow solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.51 (d, 1H, J = 2.5 Hz), 8.50 (d, 1H, J =

9.1 Hz), 7.93 (dd, 1H, J = 2.5, 8.6 Hz), 7.69 (s, 1H), 7.69-

7.28 (m, 8H), 6.89 (d, 1H, J = 8.6 Hz), 5.83 (s, 2H), 4.03 (s, 3H), 3.64 (t, 2H) J = 8.3 Hz), 0.93 (t, 2H, J = 8.3 Hz), -0.03 (s, 9H).

Example 28 (a)

6- (3-hydroxyphenyl) -3-E-styryl-1H-indazole indazole, subjected to CH 2 Cl 2).

mmol) from 1.8 ml

27 (b),

The resulting solution was minutes, then warmed to 0, and ml of sodium bicarbonate was added,

6- (3-methoxyphenyl) -3-E-styryl-1H-78 ° C and was cooled to (1.8 mmol) BBr 3 (IM solution maintained at -7 ° C ° C and held for 3 hours. 15 of the solution followed by saturated aqueous mL of ethyl acetate.

The organic layer was washed with 20 mL of brine, and then

183 concentrated under reduced pressure. Purification by silica gel chromatography gave 55 mg (59%) of 6- (3-hydroxyphenyl) -3-estyryl-1H-indazole as a white solid. ¹ H NMR (300 MHz, MeOH-dJ δ 8.16 (d, 1H, J = 8.5 Hz), 7.71-7.62 (m, 3H), 7.61-

7.44 (m, 3H), 7.43-7.35 (m, 2H), 7.33-7.25 (m, 2H), 7.20-7.10 (m, 2H), 6, 85-6.79 (m, 1H), [delta] 13.14 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1H, J = 8.4 Hz), 7.73 (s) d, 2H, J = 7, 3), 7, 64-7, 52 (m, 5H), 7, 47-7.37 (m, 3H), 7.33-7.25 (m, 1H), 6.89 (d, 2H, J = 8.6)

Hz).

Example 28 (b)

6- (4-hydroxyphenyl) -3-E-styryl-lH-indazole

6- (4-Methoxyphenyl) -3-E-styryl-1H-indazole, from Example 27 (c), was converted to 6- (4-hydroxyphenyl) -3-E-styryl-1H-indazole in a similar manner as described above. as described in Example 28 (a). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.14 (s, 1H), 9.60 (s, 1H), 8.20 (d, 1H,

J = 8.4 Hz), 7.73 (d, 2H, J = 7.3 Hz), 7.64-7.52 (m, 5H),

7.47-7.37 (m, 3H), 7.33-7.25 (m, 1H), 6.89 (d, 2H, J = 8.6)

Hz). HRMS (FAB) [M + Na] / z calcd 313.1341, measured

313.1347. Analyzed with 0.5 H ₂ O, calculated: C (78.48), H (5.33), N (8.72). Found: C (78.35), H (5.26), N (8.49).

Example 28 (c)

6- (2-hydroxy-pyridin-5-yl) -3-E-styryl-lH-indazole

184

6- (2-Methoxy-pyridin-5-yl) -3-E-styryl-1H-indazole, from Example 27 (k), was converted to 6- (2-hydroxypyridin-5-yl) -3-Estyryl-1H- indazole in a manner similar to that described in Example 28 (a). ^T H NMR (300 MHz, _DMSO-d6) δ 8.22 (d, 1 H, J =

8.4 Hz), 7.96 (dd, 1H, J = 2.6, 9.65 Hz), 7.81 (d, 1H, J = 2.0 Hz), 7.74-7.30 ( m, 9H), 6.50 (d, 2H, J = 9.4 Hz). HRMS (FAB) [M + H] / z calc. 314.1293, found 314.1280. Analyzed with 0.1 trifluoroacetic acid, calculated: C (72.69), H (4.86), N (12.59). Found: C (72.77), H (4.81), N (12.65).

Example 28 (d)

6- (3,4-dihydroxyphenyl) -3-E-styryl-lH-indazole

6- (3,4-dimethoxyphenyl) -3-E-styryl-1H-indazole, from Example 27 (j), was converted to 6- (3,4-dihydroxyphenyl) -3-E-styryl-indazole in a similar manner, as described in Example 28 (3). 1 H NMR (300 MHz, DMSO-d 6) δ 9.09 (bs, 1H), 9.07 (bs,

1H), 8.20 (d, 1H, J = 8.5), 7.73 (d, 2H, J = 7.5Hz), 7.56 (d,

2H, J = 10.1 Hz), 7.53 (s, 1H), 7.43-7.29 (m, 4H), 7.11 (s,

1H), 7.04 (d, 1H, J = 8.2 Hz), 6.86 (d, 1H, J = 8.2 Hz). HRMS (FAB) [M + H] / z calcd 329.1290, found 329.1274.

185

Analyzed with 1.0 H ₂ O, calculated: C (66, 79), H (4.73), N (7.15). Found: C (66.54), H (4.56), N (7.36).

Example 29 (a)

6-pyridin-4-yl-3-E- [2- (2,6-dichlorophenyl) ethenyl] -lH-indazole

6-pyrid-4-yl-3-E- [2- (2,6-dichlorophenyl) ethenyl] -1- (2-trimethylsilanylethoxymethyl) -1H-indazole was converted to 6-pyrid-4-yl-3-E- [ 2- (2,6-dichlorophenyl) ethenyl] -1H-indazole in a similar manner to that described in Example 27 (a). ¹ H NMR (300 MHz, CDCl ₃ ) δ 13.55 (s, 1H), 8.68 (dd, 2H, J = 4.6, 1.6 Hz), 8.21 (d, 1H, J = 8.5 Hz), 7.96 (s, 1H), 7.81 (dd, 2H, J = 4.5, 1.6 Hz), 7.66 (dd, 1H, J1 = 8.5, 1) 4 Hz), 7.58 (d, 2H, J)

8.0 Hz),

7.51 (s, 2H), 7.39-7.32 (FAB) [M + H] / z calcd

366, measured 366.

Analyzed with 0.7 H ₂ O, calculated:

N (11.09).

Measured: C

The starting material was prepared as follows:

(i) Jun *

1.20 g (5 mmol) of 2,6-dichlorobenzyl bromide was mixed with 1.66 g (10 mmol) of triethyl phosphite and heated at 150 ° C for 2 hours. The resulting mixture was then distilled at 160 ° C under reduced pressure of 10 mm Hg to remove excess triethyl phosphite. Obtained 1.46 g (100%)

186 (2,6-dichlorobenzyl) phosphonic acid diethyl ester as a colorless liquid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.33-7.28 (m,

2H), 7.15-7.07 (m, 1H), 4.14-4.02 (m, 4H), 3.60 (d, 2H, J =

22.4 Hz), 1.27 (t, 6H, J = 7.0 Hz).

Ozone was bubbled through a solution of 2.13 g (5.0 mmol) of 6-pyrid-4-yl-3-E-styryl-1- (2-trimethylsilanylethoxymethyl) -1H -indazole in 25 mL of THF and 25 mL of MeOH at -78 ° C for 15 minutes. Argon was bubbled through the solution for 10 minutes at -78 ° C, then 1.46 mL (20 mmol) of dimethyl sulfide was added. The solution was allowed to warm to room temperature and maintained for 2 hours. The solution was poured into 300 mL of brine, and then extracted with 3 x 100 mL of ethyl acetate. The organic layers were dried over MgSO ₄ , and then evaporated under reduced pressure. Purification by silica gel chromatography gave 2.2 g (75%) of 6-pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde as a white solid. ¹ H NMR (300 MHz, CDCl 3) δ 10.39 (s, 1H), 8.75 (d, 2H, J = 1.6 Hz), 8.45 (d, 1H, J = 2.8 Hz) 7.91 (s, 1H); 7.75-7.66 (m, 3H); 5.90 (s, 2H);

3.63 (t, 2H, J = 2.7Hz), 0.93 (t, 2H, J = 2.8Hz), 0.00 (s, 9H).

(Iii)

187

A solution of 582 mg (2.0 mmol) of (2,6-dichlorobenzyl) phosphinic acid diethyl ester in 15 mL of DMF was cooled to 0 ° C and treated with 160 mg (4.0 mmol) of NaH (60% in mineral oil). The resulting solution was kept at 0 ° C for 30 minutes and then treated with 353 mg (1.0 mmol) of 6-pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde. The resulting solution was allowed to warm to room temperature for 1 hour, and then held at room temperature for 2 hours. The solution was poured into 250 mL of brine, and then extracted with 3 x 80 mL of ethyl acetate. The organic layers were dried over MgSO ₄ , and then concentrated under reduced pressure. Purification by silica gel chromatography gave 330 mg (67%) of 6-pyrid-4-yl-3-E- [2- (2,6-dichlorophenyl) ethenyl] -1- (2-trimethylsilanylethoxymethyl-1H-indazole) as a yellow

oil. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.72 (dd, 2H, J = 4.6, 1.5 Hz), 8.16 (d, 1H, J = 8.5 Hz), 7.84 (s, 1H), 7.62 (ss, 2H, J = 4.5, 1.6 Hz), 7.60 (s, 2H), 7.56 (dd, 1H, J = 8.5, 1.5Hz), 7.39 (d, 1H, J = 8.1 Hz), 7.18-7.12 (m, 1H), 3.64 (t, 2H, J =

8.3 Hz), 0.92 (t, 2H, J = 8.3 Hz), 0.00 (s, 9H).

Example 29 (b)

6-pyridin-4-yl-3-E- [2- (3-methylphenyl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the desired product similar to

188 as described in Example 29 (a). ¹ H NMR (300 MHz,

MeOH-d ₄ ) 8.88 (d, 1H, J = 6.7 Hz), 8.41-8.35 (m, 3H), 8.16 (s,

1H), 7.80 (dd, 1H, J = 8.6, 1.6 Hz), 7.67-7.48 (m, 4H), 7.35 (t, 1H, J = 7.6 Hz) 7.22-7.17 (m, 1H), 4.88 (s, 3H). MS (FAB) [M + H] / z calcd 312, measured 312. Analyzed with 0.2 H ₂ O,

1.1 with trifluoroacetic acid, calcd. C (63.27), H (4.23), N (9.54). Found: C (63.08), H (4.18), N (9.80).

Example 29 (c)

6-pyridin-4-yl-3-E- [2- (4-chlorophenyl) ethenyl] -lH-indazole

Cl

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the desired product in a manner similar to that described in Example 29 (a). ^X H NMR (300 MHz, DMSO-de) δ 13.40 (s, 1H), 8.67 (dd, 2H, J = 4.6, 1.6 Hz), 8.33 '(d, 1 H, J = 8.5 Hz), 7.92 (s, 1H), 7.81 (dd, 2H, J = 4.6, 1.6 Hz), 7.78 (d, 2H, J = 8.5 Hz), 7.67-7.56 (m, 3H), 7.46 (d, 2H, J = 8.5 Hz). Analyzed with 0.15 _H2O Calc'd, C (71.81), H (4.31), N (12.56). Found: C (71.85), H (4.26), N (12.48).

Example 29 (d)

6-pyridin-4-yl-3-E- [2- (biphenyl-4-yl) ethenyl] -lH-indazole

189

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (d) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, DMSO-d 6) δ 13.40 (s, 1H), 8.68 (d, 2H, J = 4,6,1,5

Hz), 8.35 (d, 1H, J = 8.5 Hz), 7.93 (s, 1H), 7.87-7.79 (m,

4H), 7.73 (d, 4H, J = 8.1 Hz), 7.66-7.60 (m, 3H), 7.45 (m,

2H), 7.41-7.34 (m, IH). MS (FAB) [M + H] / z calcd 374, measured 374. Analyzed with 0.20 H ₂ O, calcd: C (82.82), H (5.19), N (11.15). Found: C (82.82), H (5.19), N (11.16).

Example 29 (e)

6-pyridin-4-yl-3-E- [2- (3-methoxyphenyl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (e) in a similar manner to that described in Example 29 (a). ^X H NMR (300 MHz, _DMSO-d6) δ 13.39 (s, 1H), 8.67 (d, 2H, J = 5.3 Hz);

8.33 (d, 2H, J = 8.5 Hz), 7.92 (s, 1H), 7.81 (dd, 2H, J = 4.6,

1.5 Hz), 7.65-7.54 (m, 3H), 7.35-7.28 (m, 3H), 3.83 (s, 3H).

MS (FAB) [M + H] / z calcd 328, measured 328. Analyzed with 0.20 H ₂ O, calcd: C (76.20), H (5.30), N (12.70). C (76.17), H (5.34), N (12.65).

Example 29 (f)

6-pyridin-4-yl-3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

190

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (f) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, DMSO-d 6) δ 8.68 (dd, 2H, J = 4.5, 1.6 Hz), 8.62 (d, 1H, J = 3.8 Hz), 33 (d, 1 H, J = 8.5 Hz), 7.99 (d, 1 H, J =

16.4 Hz), 7.94 (s, 1H), 7.86-7.78 (m, 3H), 7.73-7.57 (m, 3H), 7, 32-7, 26 (m , 1H). Analyzed with 0.05 _H2O Calc'd, C (76.26), H (4.75), N (18.72). Found: C (76.22), H (4.79), N (18.76).

Example 29 (g)

6-pyridin-4-yl-3-E- [2- (3-fluorophenyl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (g) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.40 (s, 1H), 8.68 (dd, 2H, J = 4.5, 1.6)

Hz), 8.34 (d, 1H, J = 8.4 Hz), 7.92 (s, 1H), 7.81 (dd, 2H, J1 = 4.5, 1.6 Hz), 7, 74-7.52 (m, 5H); 7.49-7.40 (m, 1H); 7.16 (m, 1H). MS (FAB) [M + H] / z calc 316, found 316.

Anal. Calcd. C (76.17), H (4.48), N (13.33). Found: C (76.07), H (4.53), N (13.36).

191

Example 29 (h)

6-pyridin-4-yl-3-E- [2- (2-fluorophenyl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (h) in a similar manner to that described in Example 29 (a). ^X H NMR (300 MHz, DMSO-de) δ 13.43 (s, 1H), 8.66 (dd, 2H, J = 4.5, 1.6 Hz), 8.23 (d, 1 H, J = 8.2 Hz), 7. 98-7.90 (m, 2H), 7.80 (dd,

2H, J = 4.5, 1.7 Hz), 7.73-7.54 (m, 3H), 7.40-7.31 (m, 1H),

7.30-7.21 (m, 2 H). MS (FAB) [M + H] / z calcd 316, measured 316. Anal. Calcd: C (76.17), H (4.48), N (13.33). Found: C (76.12), H (4.51), N (13.29).

Example 29 (i)

6-pyridin-4-yl-3-E- [2- (3-chlorophenyl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (i) in a similar manner to that described in Example 29 (a). ^X H NMR (300 MHz, DMSO-de) δ'13,42 (s, 1H), 8.68 (dd, 2H, J = 4.5, 1.6 Hz), 8.35 (d, 1 H, J = 8.1 Hz), 7.92 (s, 1H), 7.86 (s, 1H),

7.82 (dd, 2H, J = 4.5, 1.7 Hz), 7.74-7.51 (m, 4H), 7.43 (t, 1H, J = 7.8 Hz), 7 37-7.21 (m, IH). MS (FAB) [M + H] / z calcd

192

332, measured 332. Anal, Calc .: C (72.40), H (4.25), N (12.67) .Namer: C (72.52), H (4.28), N (12, 57).

Example 29 (j)

6-pyridin-4-yl-3-E- [2- (2-methylthiazol-4-yl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (j) in a similar manner to that described in Example 29 (a). ¹ H NMR

(300 MHz DMS0-d ₆ ) δ 13,38 (WITH, 1H), 8.67 (dd, 2H, J = 4.5, 1.6) Hz); 8.25 (d, 1 H, J = 8.5 Hz), 7, 92 (s, 1H). 7.81 (dd, 2H, J = 4.5. 1.6 Hz), 7 70 to 7.50 (M, 4H), 2.72 (s, 3H). MS (FAB)

[M + H] / z calcd 319, measured 319.

Analyzed with 0.15

H (4.25), N trifluoroacetic acid, calculated: C (65.51), (16.70). Found: C (65.56), H (4.37), N 16.53).

Example 29 (k)

6-pyridin-4-yl-3-E- [2- (naphthalen-2-yl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (k) in a similar manner to that described in Example 29 (a). ^X H NMR

193

(300 MHz, _DMSO-d6) δ 13.40 (s, 1H), 8.68 (dd, 2H, J = 4.6, 1.4 Hz), 8.39 (d, 1 H, J = 8.5 Hz), 8.17 (s, 1H), 8.09 -7.89 (M, 8H), 7.83 (dd, 2H, J = 4, 6, 1.6 Hz), 7.74 (s, 2H). 7, 65 (Dd, 1H, J = 8.5, 1.4 Hz), 60, 60-7, 46 (m, 4H). MS (FAB ) [M + H] / z calculated 348, measured 348. analyzed with 1, 05

trifluoroacetic acid, calculated: C (67.10), H (3.89), N (9.00). Found: C (67.20), H (3.93), N (9.05).

Example 29 (1)

6-pyridin-4-yl-3-E- [2- (2,3-difluorophenyl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (1) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, CDCl ₃ + MeOH-d ₄ ) δ 8.68 (d, 2H, J = 5.6 Hz,), 8.02 (d, 1H, J = 8.5 Hz), 7 70 (s, 1H), 7.58 (dd, 2H, J = 4.8, 1.5 Hz), 7.57-7.39 (m, 3H), 7.38-7.31 (m 1 H, 7.06-6.96 (m, 2H).

MS (FAB) [M + H] / z calcd 334, measured 334. Analyzed with 0.80 H ₂ O, calcd: C (69.08), H (4.23), N (12.08). Found: C (68.77), H (3.93), N (11.85).

Example 29 (m)

6-pyridin-4-yl-3-E- [2- (3,5-difluorophenyl) ethenyl] -lH-indazole

194

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (m) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, MeOH-d ₄ ) δ 8.69 (d, 2H, J = 6.3 Hz), 8.34 (d, 1H, J =

8.5 Hz), 7.97 (s, 1H), 7.97 (d, 2H, J = 6.3 Hz), 7.71 (d, 1H, J = 10.0 Hz), 7.62 (s IH), 7.60 (s, 1H), 7.36 (d, 1H, J = 11.11), 6.95-6.89 (m, 1H). MS (ES) [M + H] / z calcd 334, measured 334. Anal, calcd: C (72.06), H (3.93), N (12.61). Found: C (72.20), H (4.01), N (12.58).

Example 29 (n)

6-pyridin-4-yl-3-E- [2- (biphenyl-3-yl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (n) in a similar manner to that described in Example 29 (x). ^X H NMR (300 MHz, DMSO-de) δ 8.68 (d, 2H, J = 6.1 Hz), 8.39 (d, IH, J = 8.5), 8.04 (s, H 7.92 (s, 1H), 7.82 (d, 2H, J = 6.2 Hz), 7.79-7.37 (m, 11H). MS (ES) [M + H] / z calcd 374, measured 374. Anal. Calcd: C (83.62), H (5.13), N (11.25). Found: C (83.47), H (5.08), N (11.32).

Example 29 (o)

6-pyridin-4-yl-3-E- [2- (2,6-difluorophenyl) ethenyl] -lH-indazole

195

6-pyridin-4-yl-l- (2-trimethylsilanyl-ethoxymethyl) -lH-indazole

3-Carbaldehyde was converted to the compound of Example 29 (o) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, MeOH-dJ δ 8.69 (d, 2H, J = 6.3 Hz), 8.21 (d, 1H, J =

8.6 Hz), 7.97 (s, 1H), 7.88 (d, 2H, J = 6.3 Hz), 7.83 (d, 1H, J = 17.1 Hz), 7.71 (1H, J = 8.6Hz), 7.65 (d, 1H, J = 17.1)

Hz), 7.40-7.35 (m, 1H), 7.13-7.08 (m, 2H).

MS (ES) [M + H] / z calc 334, measured 334.

Analyzed with 0.1 H ₂ O, calculated:

C (71.67), H (3.97),

N (12.54).

Found: C (71.37), H (3.90), N (12.31).

Example 29 (p)

6-pyridin-4-yl-3-E- [2- (3-trifluoromethoxy-phenyl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (p) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.84 (d, 2H, J = 6.4 Hz), 8.43 (d, 1H, J =

8.5 Hz), 8.19 (d, 2H, J = 6.4 Hz), 8.07 (s, 1H), 7.81-7.27 (m, 5H), 7.78 (s, 1H). MS (ES) [M + H] / z calcd 382, measured 382. Analyzed with 1.0 trifluoroacetic acid, calcd: C (55, 76), H (3.05), N (8.48). Found: C (55.84), H (3.09), N (8.45).

196

Example 29 (q)

6-pyridin-4-yl-3-E- [2- (benzimidazol-2-yl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (q) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, DMSO-d 6) δ 8.69 (d, 2H, J = 6.1 Hz), 8.25 (d, 1H, J =

8.5 Hz), 8.03 (d, 1H, J = 16.7 Hz), 7.97 (s, 1H), 7.84 (d, 2H, J = 6.2), 7.72 ( d, 1H, J = 8.5 Hz), 60-7.57 (m, 2H), 7.53 (d, 1H, J = 16.7 Hz), 7.22-7.19 (m , 2H). MS (ES) [M + H] / z calc. 338, measured 338. Analyzed with 2.0 trifluoroacetic acid, 0.2 H ₂ O, calculated: C (52.77), H (3.08), N ( 12,31). Found: C (52.59), H (3.17), N (12.18).

Example 29 (r)

6-pyridin-4-yl-3-E- [2- (3,4-methylenedioxyphenyl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (r) in a similar manner to that described in Example 29 (a). ^X H NMR (300 MHz, DMSO-de) δ 8.67 (d, 2H, J = 6.1 Hz), 8.30 (d, 1 H, J =

8.5 Hz), 7.89 (s, 1H), 7.81 (d, 2H, J = 6.1 Hz), 7.61 (d, 1H, J = 9.9 Hz), 7.46 -7.42 (m, 3H), 7.18 (d, 1H, J = 9.6 Hz), 6.95 (d, 1H, 8.0 Hz), 6.05 (s, 2H). MS (ES) [M + H] / z calcd 342,

197 measured 342. Anal. Calc .: C (73.89), H (4.43), N (12.31). Found: C (73.74), H (4.52), N (12.40).

Example 29 (s)

6-pyridin-4-yl-3-E- [2- (2,5-difluorophenyl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (s) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, MeOH-d 6) δ 8.53 (d, 2H, J = 6.0 Hz), 8.03 (d, 1H, J =

8.5 Hz), 7.60 (d, 2H, J, 2 Hz), 7.5-7.35 (m, 3H), 7.34-7.26 (m, 1H), 7.03- 6.93 (m, 1H); 6.90-6.81 (m, 1H). MS (ES) [M + H] / z calc. 334, measured 334. Analyzed with 0.30 H ₂ O, calculated: C (70.91), H (4.05), N (12.37). Found: C (70.97), H (4.17), N (12.37),

Example 29 (t)

6-pyridin-4-yl-3-E- [2- (lH-pyrrol-2-yl) ethenyl] -lH-indazole

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (t) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, MeOH-dJ δ 8.60 (d, 2H, J = 6.3 Hz), 8.13 (d, 1H, J =

8.5 Hz), 7.86 (s, 1H), 7.79 (d, 2H, J = 6.2 Hz), 7.57 (dd, 1H,

198

J1 = 8.5 Hz, J2 = 1.5 Hz), 7.40 (d, 1H, J = 16.8 Hz), 7.09 (d, 1H, J = 16.7 Hz), 6.77 -6.82 (m, 1H), 6.40-6.35 (m, 1H), 6.16 (t, 1H, J = 2.9 Hz). MS (ES) [M + H] / z calc. 287, measured 287. Analyzed with 0.5 ethyl acetate, 0.3 tetrahydrofuran, 0.1 hexane, 0.1 ethylenediamine, calculated: C (72.07), H ( 6.21), N (16.05). Found: C (71.95), H (6.20), N (15.76).

The starting material was prepared as follows:

H (i) A solution of 9.5 g (100 mmol) of 1H-pyrrole-2-carbaldehyde and 500 ml of THF was cooled in an ice bath. It was added 19.2 g (200 mmol) of Bu ^PART ONa and the reaction stirred at 0 DEG C. for 1 h. Then 32.7 g (150 mmol) of MtsCl was added. The reaction mixture was allowed to warm to room temperature and maintained for 2 hours at room temperature. The solution was then treated with 100 mL of saturated aqueous NH ₄ Cl, and the mixture was poured into 2 L of brine. The mixture was extracted with 3 x 300 mL EtOAc. The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography to give 15.7 g (57%) of 1- (2,4,6-trimethylbenzenesulfonyl) -1H-pyrrole-2-carbaldehyde as a pale yellow oil. ^{Τ Η} NMR (CDC1 ₃₎ δ 9.50 (s,

1 H, 7 79-7, 74 (m, 1 H), 7.12 (dd, 1 H, J = 3.7, 1.8 Hz), 6.95 (s, 2 H), 6.38 (t 1 H, J = 3.4 Hz), 2.50 (s, 6H), 2.30 (s, 3H).

OH

MT ·

199 (ii) 2.77 g (10 mmol) of 1- (2,4,6-trimethylbenzenesulfonyl) -1H-pyrrole-2-carbaldehyde in 100 mL of THF was treated with 0.44 g (20 mmol) of LiBH ₄ at room temperature. The resulting solution was kept at room temperature for 1 hour. Then 10 mL of MeOH was added and the resulting mixture was poured into 600 mL of brine and extracted with 3 x 200 mL of EtOAc. The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure. The resulting oil was then purified on a silica gel column to give 2.43 g (870) of [1- (2,4,6-trimethylbenzenesulfonyl) -1H-pyrrol-2-yl] methanol as a light brown oil. ^X 1 HNMR (CDCl ₃₎ δ 7.17 (dd, 1 H, J = 3.3, 1.8 Hz), 6.99 (s, 2H), 6. 28 to 6.23 (m, IH); 6.18 (t, 1H, J = 3.3 Hz), 4.42 (s, 2H), 2.50 (s, 6H, 2.30 (s, 3H)).

MTe (iii) A solution of 1.4 g (5.0 mmol) of [1- (2,4,6-trimethyl-benzenesulfonyl) -lH-pyrrol-2-yl) methanol in 25 ml of CHC1 ₃ was cooled in an ice bath. 1.1 mL (15 mmol) of SOCl ₂ was added slowly. The solution was allowed to warm to room temperature and held for an additional 45 minutes. The solution was then concentrated under reduced pressure. 1.5 g (100%) of 2-chloromethyl-1- (2,4,6-trimethylbenzenesulfonyl) -ΙΗ-pyrrole was obtained as a brown solid. ^R 1 HNMR (CDCl ₃₎ δ 7.28 (d, IH, J = 3.3, 1.7 Hz), 6.98 (s, 2H), 6. 38-6. 34 (m, H), 6.19 (t, 1H, J = 3.4Hz), 4.58 (s, 2H),

2.50 (s, 6H); 2.30 (s, 3H).

Example 29 (u)

6-pyridin-4-yl-3-E- [2- (3-metylkarbamoylmetoxyfenyl) ethenyl) -1Hindazol

200

6-Pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde was converted to the compound of Example 29 (u) in a similar manner to that described in Example 29 (a). ¹ H NMR (300 MHz, MeOH-d ₄ ) δ 8.68 (d, 2H, J = 5.9 Hz), 8.51 (bs, 1H),

8.37 (d, 1H, J = 8.5 Hz), 8.19 (s, 1H), 7.93 (s, 1H), 7.87 (d, 1H, J = 7.7 Hz), 7.85 (d, 2H, J = 6.1 Hz); 7.62 (d, 1H, J =

8.1 Hz), 7.65-7.63 (m, 3H), 7.51 (t, 1H, J = 7.6 Hz). MS (ES) [M + H] / z calcd 355, measured 355. Analyzed with 0.4 trifluoroacetic acid, 0.50 H ₂ O, calcd: C (69.67), H (4.98), N ( 14,26). Found: C (69.78), H (5.18), N (14.08).

Example 30 (a)

6- [3-benzamidophenoxy] -3-E- [2- (thien-2-yl) ethenyl] -lH-indazole

Example 30 (a) was prepared in a similar manner to Example 6 (a) except that (E) -3-thiophen-2-yl-acryloyl chloride was used in place of 3- (4-chlorophenyl) acryloyl chloride in step (i). ¹ H NMR (DMSO-d 6) δ 13.05 (s, 1H),

10. 33 (s, 1H), 8.19 (d, 1H , J = 8.8 Hz), 7.92 (d, 2H, J = 6.9 Hz) , 7.70 (d, 1 H, J = 16 5 Hz) 7.65-7.49 (m, 6H); 7.40 (T, 1H, J = 8 1 Hz), 7.35 (with, 1H, p subdivision), 7.20 (d, 1H, J =  16.5 Hz), 7.10 (m, 1H), 7, 04 (s, 1H), 6.98 (d, 1 H, J = 8.8 Hz) , 6.86 (s, 1 H, J = 9.8 Hz). Anal. calculation for C ₂₆ H ₁₉ N ₃ O ₂ S ·

201

0.6 H ₂ O: C, 69.65, δ, 4.54, N, 9.37, S, 7.15. Measured: C,

69.77, H, 4.45, N, 9.52, S, 7.02.

Example 30 (b)

6- [3- (pyrrol-4-ylcarboxamido) phenoxy] -3-E- [2- (4-chlorophenyl) ethenyl] -lH-indazole

Cl ^ SSS / N-NH * compound from the example 30 (b) was prepared similarly way has been described for Example 6 (a) except that

1-Acetylpiperidine-4-carboxylic acid and HATU were used instead of benzoyl chloride in step (ii). ¹ H NMR (DMSO-d ₆ ) (J =

8.6 Hz) δ 7.76, (d, J = 8.6 Hz), 7.53 (d, J = 6.2 Hz), 7.46 (d, J = 8.4 Hz), 7 37 (m, 3H), 7.01 (s, 1H, finely divided),

6.97 (d, J = 8.8 Hz), 6.78 (d, J = 7.7 Hz), 4.38 (m, 1H), 3.85 (m, 1H), 3.09- 2.96 (m, 1H); 2.58 (m, 2H); 1.99 (s, 3H); 1.77 (m, 2H); 1.55 (m, 1H); 1.37 (m) , 1H). Anal. Calcd for C 29 H 27 ClN ₄ O 3 · 1/3 H ₂ O: C, 64.69, H, 5.54, N, 10.41. Found: C, 64.64, H, 5.51, N, 10.23.

Example 30 (c)

6- [3-Benzamidophenoxy] -3-E- [2- (fur-2-yl) ethenyl] -1H-indazole

202

The compound of Example 30 (c) was prepared in a similar manner to Example 6 (a) except that (E) -3-furan-2-ylacryloyl chloride, prepared according to Collect, Czech. Chem. Comm., 52, 409-24, 1987) was used instead of 3- (4-chlorophenyl) acryloyl chloride in step (i). ¹ H NMR (DMSO-d 6) δ 13.00 (s, 1H), 10.32 (s, 1H), 8.14 (d, 1H, J = 8.8 Hz), 7.91 (d, 2H) J = 7.0 Hz), 7.73 (s, 1H), 7.70-7.51 (m, 5H), 7.40 (t,

1H, J = 8.4Hz), 7.30 (AB, 2H, J = 16.7Hz), 7.04 (s, 1H),

6.98 (d, 1H, J = 8.7 Hz), 6.86 (d, 1H, J = 8.0 Hz), 6.65 (s, 1H, finely divided), 6.60 (s (1H, finely divided). Anal. Calcd for C 26 H ₁₉ N ₃ O ₂ · 0.7 H ₂ O: C, 71.94, H, 4.74, N, 9.68. Found: C, 72.17, H, 4.83, N, 9.44.

Example 30 (d)

6- [3- (indol-4-ylcarboxamido) phenoxy] -3-E-styrylindazol

from Example 30 (d)

The compound was prepared in a similar manner to that described in Example 30 (a) using

3- (styryl-1H-indazol-6-yloxy) phenylamine instead of 3- (3-styryl-

4,5-dihydro-1H-indazol-6-yloxy) phenylamine and 1H-indole-4-carboxylic acid in place of benzoic acid in step (ii). ^T H NMR (DMSO-de) δ 12.99 (s, 1H), 11.33 (s, 1H), 10.24 (s, 1H).

8.22 (d, 1 H, J = 8.7 Hz), 7.72-7.38 (m, 10 H), 7.30 (d, 1 H, J =

7.1 Hz), 7.19 (m, 2H), 7.04 (m, 3H), 6.82 (m, 2H). Anal. Calcd for C 30 H ₂₂ N ₄ O ₂ · 0.6 H ₂ O: C, 74.86, H, 4.86, N, 11.64.

Found: C, 74.90, H, 5.01, N, 11.33.

Example 30 (e)

203

6- [3 - ((l-ethyl-3-methyl-lH-pyrazol-5-yl) carboxamido) phenoxy] -3-Estyrylindazol

Example 30 (e) was prepared in a similar manner to that described in Example 30 (a) using

3- (styryl-1H-indazol-6-yloxy) phenylamine instead of 3- (3-styryl-

4,5-dihydro-1H-indazol-6-yloxy) phenylamine and 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid instead of benzoic acid in step (ii).

Example 31 (a)

6- [3-benzamidophenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

To a stirred solution of 492 mg (1.13 mmol) of 6- [3-benzamidophenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -4,5-dihydro-1H-indazole in 15 mL of 1, 4-Dioxane was added 386 mg (1.7 mmol) of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ). The reaction mixture was stirred. for 30 minutes at room temperature, then poured into saturated NaHCO ₃ solution and EtOAc. The layers were separated and the aqueous layer was extracted again with EtOAc. The combined organic layers were washed successively with saturated NaHCO ₃ solution and saturated NaCl solution, dried over MgSO _4, and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel, eluting with CH ₂ Cl ₂ / EtOAc: MeOH (1: 1: 0.1). The oil obtained was triturated from

204 of EtOAc / hexane gave 420 mg (86%) of the title compound as a yellow-brown solid. ¹ H NMR (DMSO-d 6) δ 13.12 (s, 1H), 10.30 (s, 1H), 8.60 (d, 1H, J = 3.8 Hz), 8.22 (d, 1H) J = 8.8 Hz), 7.93 (m, 3H), 7.82 (t, 1H, J = 7.7 Hz), 7.68-7.49 (m, 7H), 7.40 (t, 1H, J = 8.1Hz), 7.27 (m, 1H), 7.08 (s, 1H), 7.03 (s, 1H), 7.03 (d, 1H, J = 8.7 Hz), 6.87 (d, 1H, J = 8.1 Hz, fine resolution). Anal. Calcd for C 27 H 20 N 4 O 2 • 0.65 EtOAc: C, 72.59, H, 5.19, N, 11.44. Found: C, 72.34, H, 5.11, N, 11.82.

The starting material was prepared as follows:

Step (s)

1) UHMDS

(2) (E) -3-pyridin-2-ylacroyl chloride hydrochloride

3) NA · HjO

A solution of 4.00 g (10.9 mmol) of 3- [3- (benzhydrylidenamino) phenoxy) cyclohex-2-enone in 20 mL of THF was added slowly to a solution of 36 mL of LiHMDS (1.0 M solution in THF) at 78 ° C. C. 15 minutes after the addition was complete, (E) -3-pyridin-2-ylacryloyl chloride hydrochloride was added and stirring was continued at 78 ° C for 30 minutes. The reaction was quenched with saturated NH ₄ Cl solution and extracted with 3xEtOAc. The combined organic layers were washed with saturated NaCl solution, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel, eluting with hexane / EtOAc (2: 1). The appropriate fractions were concentrated under reduced pressure and dissolved in 8 mL of a 1: 1 mixture of EtOH and HOAc. To this solution was added hydrazine hydrate (3.4 mL, 70.0 mmol) at 80 ° C. After 15 minutes, all starting material was worked up and the reaction mixture was carefully poured into saturated NaHCO ₃ and extracted with 2 x EtOAc.

205

The combined organic layers were washed with saturated NaCl solution, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel eluting with CH ₂ Cl ₂ / MeOH (9: 1) to give 676 mg (19%) of 6- (3-aminophenoxy) -3-E- [2- (pyridine-2-) yl) ethenyl) -4,5-

dihydro-indazole . ^X H NMR (DMSO-d ₆ ) δ 12.51 (s, 1H), 8 57 (d, 1 H, J = 3.8 Hz), 7, 78 (t, 1H, J = 7.8) Hz), 7.51 (M, 2H) , 7.25 (m, 1 H), 7.05 (m, 2H) 6.35 (d, 1 H, J = 7.9 Hz, with j emným divided), 6.32 (t, 1H, J = 2.1 Hz), 6, 23 (d, 1 H, J = 7 9 Hz), 5.54 (s, 1 H), 5.23 (with, 2H), 2.95 (t, 2H, J = 8.2) Hz), 2 60 (t, 2H, J = 8.2Hz), MS [M + H] / z calcd 331. N American Christians : 331. Anal. calculation for C ₂₀ H! _θ Ν ₄ Ο · 0.15 H ₂ O: C, 72.12, H, 5 54, N, 16.82. Measured: C, 72. 11, H, 5.55, N, 16.61.

Step (ii)

To a stirred solution of 350 mg (1.06 mmol) of dihydroaniline and 776 mg (6.36 mmol) of benzoic acid in 15 mL of DMF was added

2.42 g (6.36 mmol) of HATU and 1.8 mL (12.71 mmol) of NEt3. The reaction mixture was heated at 50 ° C for 1.5 hours, cooled and poured into a mixture of ice and saturated NaCl solution. Ppt was collected by vacuum filtration, washed with H ₂ O and air dried. To this filter cake dissolved in 10 mL of MeOH / THF (1: 1) was added 650 mg of K ₂ CC 3 and 1 mL of H ₂ O. After 1 hour, the reaction mixture was poured into saturated NaCl solution and extracted with 2 x EtOAc. The combined organic layers were washed with saturated NaCl solution, dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel, eluting with CH ₂ Cl ₂ / EtOAc / MeOH

206 (1: 1: 0.1) to give 333 mg (72%) of 6- [3-benzamidophenoxy] -3-E [2- (pyridin-2-yl) ethenyl] -4,5-dihydro-1H- indazole. ¹ H NMR (DMSO-d 6) δ 12.58 (bs, 1H), 10.34 (s, 1H), 8.57 (d, 1H, J =

3.8 Hz), 7.95 (d, 2H, J = 6.8 Hz), 7.81-7.70 (m, 2H), 7.63-

7.50 (m, 6H), 7.40 (t, 1H, J = 8.1Hz), 7.25 (m, 1H), 7.09 (d,

1H, J = 16.3 Hz), 6.89 (d, 1H, J = 8.0 Hz), 5.64 (s, 1H), 2.99 (t, 2H, J = 8.1 Hz) 2.66 (t, 2H, J = 8.1Hz). Anal. Calcd for C ₂₇ H ₂₂ N ₄ O ₂ · 0.1 CH ₂ Cl ₂ : C, 73, 48, H, 5.05, N, 12.65. Found: C, 73.48, H, 5.05, N, 12.48.

Example 31 (b)

6- [3 - ((1,5-dimethyl-lH-pyrazol-3-yl) carboxamido) phenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 31 (b) was prepared in a similar manner to that described in Example 31 (a) except that

1,5-Dimethyl-1H-pyrazole-3-carboxylic acid was used in place of benzoic acid in step (ii). ¹ H NMR (DMSO-d 6) δ

13.13 (s, 1H), 10.07 (s, 1H), 8.60 (d, 1H, J = 4.3 Hz), 8.21 (d, 1H, J = 8.7 Hz), 7.93 (d, 1H, J = 16.3 Hz), 7.82 (t, 1H, J = 7.4 Hz), 7.69 (m, 3H), 7.56 (d, 1H, J = 16.3 Hz), 7.32 (m, 2H), 7.05 (s, 1H), 7.01 (d, 1H, J = 8.7 Hz), 6.80 (m, 1H),

6.52 (s, 1H); 3.81 (s, 3H); 2.29 (s, 3H). Anal. Calcd for C ₂₆ H ₂ N ₆ O 2 · 0.1 CH ₂ Cl ₂ / 0.1 hexane: C, 68.58, H, 5.09, N, 17.97.

Found: C, 68.26, H, 5.25, N, 17.61.

Example 31 (c)

207

6- [3 - ((5-ethylsulfonylthien-2-yl) carboxamido) phenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

The compound of Example 31 (c) was prepared in a similar manner to that described in Example 31 (a) except that

5-Methanesulfonyl-thiophene-2-carboxylic acid was used in place of benzoic acid in step (ii). ¹ H NMR (DMSO-d 6) δ

13.17 (s, 1H), 10.58 (s, 1H), 8.61 (d, 1H, J = 4.0 Hz), 8.24 (d, 1H, J = 8.8 Hz), 8.05 (d, 1H, J = 4.1Hz), 7.97-7.79 (m,

3H), 7.68 (d, 1H, J = 7.8Hz), 7.66-7.48 (m, 3H), 7.43 (t, 1H,

J = 8.2 Hz), 7.28 (m, 1H), 7.10 (s, 1H, fine separation), 7.00 (d, 1H, J = 8.7 Hz), 6.92 ( d, 1H, J = 8.1 Hz, fine resolution), 3.41 (s, 3H). Anal. Calcd. For C 26 H 20 N 4 O 4 S 2 · 0.4

EtOAc: C, 60.07, H, 4.24, N, 10.15, S, 11.62. Found: C, 60.22, H, 4.48, N, 10.05, S, 11.49.

Example 31 (d)

6- [3 - ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) phenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

208

The compound of Example 31 (d) was prepared in a similar manner to that described in Example 31 (a) except that 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid was used in place of benzoic acid in step (ii) ). ¹ H NMR (DMSO-d ₆ ) δ 13.15 (s, 1H), 10.18 (s, 1H), 8.61 (d, 1H, J = 3.7 Hz), 8.22 (d, 1H, J = 8.8Hz), 7.94 (d, 1H, J = 16.3Hz), 7.82 (t, 1H, J = 7.5Hz), 7.67 (d, 1H, J = 7.7 Hz), 7.55 (m, 3H), 7.40 (t,

1 H, J = 8.1 Hz), 7.28 (m, 1H), 7.06 (s, 1H), 7.01 (d, 1H, J =

8.8 Hz), 6.89 (d, 1H, J = 7.9 Hz), 6.78 (s, 1H), 4.38 (q, 2H, J = 7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz). Anal. Calcd for C 27 H 24 N 6 O 2 · 0.6 EtOAc: C, 68.25, H, 5.61, N, 16.24. Found: C, 68.28, H, 5.88, N, 16.01.

Example 31 (e)

6- [3 - ((l-methylimidazol-2-yl) carboxamido) phenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example (e) was prepared in a similar manner to that described in Example 31 (a) 1-methyl-1H-imidazole-2-carboxylic acid except that it was used in place of benzoic acid in step (ii). ^{Χ Η} NMR (DMSO-d₆) δ

13.1 3 (s, 1H), 10.47 (with, 1H), 8.60 (d , 1H,  J = 3.9 Hz), 8.21 (D, 1H, J = 8.7 HZ), 7.93 (d, 1 H, J = 16.3 Hz), 7.82 (t, 1 H, J = 7, 6 Hz) , 7.65 (m, 3H), 7.56 (d, 1H, J = 16, 3 Hz), 7.43 (s, 1H), 7.37 (t, 1 H, J = 8, 1 Hz), 7 28 (M, 1H), 7.04 (m, 3H) 6, 84 (D, 1 H, J = 7, 7 Hz ), 3.95 ( with, 3H). TINAL . calculation for

C25H20N6O2

0.4 H ₂ O: C, 67.49, H, 4.80,

N, 18.65. Measured: C,

67, 68, H, 4.73, N, 18.94.

209

Example 31 (f)

6- [3 - ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) phenoxy] -3E- [2- (1,2-dimethyl-1H-imidazol-4-yl) ethenyl] -lH-indazole

The compound of Example 31 (f) was prepared in a similar manner to that described in Example 31 (a) except that (E) -3- (1,2-dimethyl-1H-imidazol-4-yl) acryloyl chloride hydrochloride was substituted in place of (E) -3-pyridin-2ylakryloylchloridu in step (i) and l-ethyl-3-methyl-lH-pyrazole-5-carboxylic acid used in place of benzoic acid in step ^{(ii); H} NMR (DMSO-de) δ 12.82 (s, 1H), 10.17 (s, 1H),

8.05 (D, 1 H, J = 8, .8 Hz), 7.58 (d, 1H, , J = 8, 4 Hz), 7.48 (s, 1H), 7, 38 (t, 1 H, J = 8.1 Hz), 7.25 (with, 2H); 7.20 (s, 1 H), 7.01 (with, 1H), 6.92 (d, 1H, J = 8.7Hz) ), 6, , 85 (d, 1 H, J = 8.7 Hz), 6.78 (s, 1 H), 4.37 (q, 2H, J = 7.0 Hz), 3, 56 (s, 3H) 2.31 (with, 3H), 2.19 (s, 3H), 1.29 (t, 3H, J = 7.0 Hz ). Anal.

Calcd for C27H27N7O2 · 1.0 H ₂ 0 · 0.3 EtOAc: C, 64.39, H, 6.02,

N, 18.64. Found: C, 64.52, H, 5.98, N, 18.52.

Example 32 (a)

6- [3-Benzamidophenoxy] -3-E- [2- (1H-imidazol-4-yl) ethenyl] -1H-indazole

210

To a stirred solution of 213 mg (0.39 mmol) of 6- (3-benzamidophenoxy) -3-E- [2- (1- (2-trimethylsilanylethoxy) methyl-imidazol-4-yl) ethenyl] -ΙΗ-indazole in 5 mL of THF 6.0 mL (6.0 mmol) of 1.0 M TBAF in THF and 0.26 mL (3.86 mmol) of ethylenediamine were added. After heating at 70 ° C for 18 hours, the reaction mixture was cooled, diluted with EtOAc and washed repeatedly with saturated NaHCO 3 solution. The organic layer was dried over MgSO ₄ and concentrated under reduced pressure. The residue was subjected to flash chromatography on silica gel eluting with CH ₂ Cl ₂ : EtOAc: MeOH (1: 1: 0.2). The obtained oil was triturated from EtOAc / hexane to give 65 mg (40%) of AG13853. ¹ H NMR (DMSO-d 6) δ 12.90 (s, 1H), 12.35 (s, 1H), 10.32 (s, 1H), 8.08 (d, 1H, J = 8.7 Hz) 7.91 (d, 2H, J = 6.8 Hz), 7.81 (s, 1H),

7.44-7.31 (m, 4H), 7.03 (s, 1H), 6.96 (d, 7H);

1H, J = 8.7 Hz), 6.85 (d, 1H, J = 8.1 Hz). Anal. Calcd for C ₂₅ H ₉ N ₅ O ₂ · 0.7 H ₂ O · 4.4 EtOAc: C, 68.07, H, 5.07, N, 14.92.

Found: C, 67.93; H, 4.89; N, 15.06.

The starting material was prepared in a similar manner to that described in Example 31 (a) except that (E) - [1- (2-trimethylsilanyl) ethoxymethyl) -1H-imidazol-4-yl] acryloyl chloride hydrochloride was used in place of the hydrochloride (E). 3-pyridin-2-ylacryloyl chloride in step (i).

Example 32 (b)

6- [3 - ((l-ethyl-3-methyl-lH-pyrazol-5-yl) carboxamido) phenoxy] -3-E [2- (lH-imidazol-4-yl) ethenyl] -lH-indazole

hl

211

The compound of Example 32 (b) was prepared in a similar manner to that described in Example 32 (a) except that 1-ethyl-3-methyl-1H-pyrazole-5-carboxylic acid was used in place of benzoic acid in step (ii) ). ^X H NMR (DMSO-de) δ

12.89 (s, 1 H), 12.37 (s, 1 H), 10.18 (s, 1 H), 8.07 (d, 1 H, J =

8.9 Hz), 7.74 (s, 1H), 7.58 (d, 1H, J = 8.3 Hz), 7.49 (s, 1H), 7.44-732 (m, 3H) 7.28 (s, 1H); 7.01 (s, 1H); 6.95 (d, 1H, J =

8.9 Hz), 6.86 (d, 1H, J = 8.6 Hz), 6.78 (s, 1H), 4.38 (q, 2H, J = 7.1 Hz), 2.19 (s, 3H), 1.29 (t, 3H, J = 7.1 Hz). Anal. Calcd for C 25 H 23 N ₇ O ₂ · 0.8 H ₂ O · 0.1 EtOAc: C, 63.99, H, 5.37, N, 20.57. Found: C, 63.72; H, 5.12; N, 20.25.

Example 32 (c)

6- [3 - ((l-ethyl-3-methyl-lH-pyrazol-5-yl) carboxamido) phenoxy] -3-E [2- (2-methylimidazol-4-yl) ethenyl] -lH-indazole

The compound of Example 32 (c) was prepared in a similar manner to that described in Example 32 (b) except that (E) -3- [2-methyl-1- (2-trimethylsilanyl) ethoxymethyl) -1H-imidazole- 4-yl] acryloyl chloride was used instead of (E) -3- [1- (2-trimethylsilanyl) ethoxymethyl) -1 ^X H NMR (DMSO-de) δ imidazol-4-yl] acryloyl chloride in step (i).

12.85 (w, 1H), 11.80 (b s, 1H) 10.18 (s, 1H), 8.05 (d, 1H, J = 8.7 Hz) 7.58 (d, 1 H, J = 8.4 Hz), 7.48 (s, 1H) 7.39 (T, 1H, J = 8.2 Hz), 7.33-7.05 (m, 4H) , 7.00 (s, 1H), 6.93 (d, 1H,

212

J = 8.7 Hz), 6.86 (d, 1H, J = 8.2 Hz), 6.78 (s, 1H), 4.38 (q, 2H, J = 7.1 Hz), 2 31 (s, 3H), 2.19 (s, 3H), 1.29 (t, 3H, J =

7.1 Hz). Anal. Calcd for C 26 H 25 N ₇ O ₂ · 0.9 H ₂ · 0.4 EtOAc: C, 63.87, H, 5.83, N, 18.89. Found: C, 63.64, H, 5.76, N, 18.85.

Example 33 (a)

6- [2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] indazole

Example 33 (a) was prepared from 6- [2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ- indazole in a similar manner to that described for Example 11. R f sm 0.8, p 0.15 (ethyl ^acetate); H NMR (300 MHz, DMSO-de) δ 13.45 (s, 1H), 8.72 ( d, 1H, J = 3.9 Hz), 8.47 (m, 1H), 8.31 (d, 1H, J = 8.5 Hz), 8.06 (d, 1H, J = 16.4) Hz), 7.92 (dt, 1H, J = 1.7, 7.6 Hz), 7.78 (d, 1H, J = 7.8 Hz), 7.71 (s, 1H), 7, 68 (d, 1 H, J = 16.5)

Hz), 7.61 (dd, 1H, J) = 1.7 (7.2 Hz), 7.45-7.36 (m, 4H) , 7.31 (d, 1H, J = 8.5Hz) 7.17 (m, 1H); 2.89 (d, 3H, J = 4, 6 Hz), ¹³ C NMR (75 MHz, DMSO) -d ₆ ) δ 167, 8, 154, 8, 149, 141.9, 141.8. 137, 136, 8, 135, 4, 132.5. 130.2, 130.0, 129.2, 127.7. 126.1.

125, 4, 123.5, 122.5, 122.4, 121, 6, 1202, 114, 5, LCMS (100% area) Rt = 3.5 min (pos) [M + H] / z calcd 387 Analyzed with 0.1 H ₂ O, 0.1 EtOAc calculated: C (67.78), H (4.82), N (14.11), S (8.08). Found: C (67.78), H (4.77), N (14.06), S (8.08).

The starting material was prepared as follows:

213 i

In an argon atmosphere, 30.0 g (62.9 mmol) of 6-iodo-3-styryl-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole prepared in Example 14, step (i), was dissolved in 375 ml of dichloromethane and cooled to -42 ° C in an acetonitrile and dry ice bath. Ozone (1 L / min, 60 V, 1.8 A) was then bubbled through the mixture for 45 minutes. Standard indicators did not indicate a clear color change relative to the background color of the solutions. To avoid excessive oxidation, the progress of the reaction was monitored by TLC (1: 9 EtOAc / hexane). The addition of ozone was stopped and the flask was filled with argon. Then, 30 mL of dimethylsulfide was added and the mixture was allowed to warm to 23 ° C. The mixture was stirred for 4 hours and was concentrated under reduced pressure. The oil was placed under high vacuum for 16 hours. The residue was dissolved in 15 mL of dichloromethane and diluted with 100 mL of hexane to give a few crystals (no desired product). The mixture was filtered and the filtrate was concentrated. The residue was dissolved in 250 mL of a 8: 2 mixture of hexane and EtOAc, treated with 50 mL of silica gel, filtered and concentrated. After 72 hours under high vacuum, 24.17 g (~ 95% pure by NMR, 91% yield) of 6-iodo-3-carboxaldehyde-1- [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole were obtained as a yellow solid: R _f sm 0.34, p 0.29 (ethyl acetate-hexane 1: ^9); H NMR (300 MHz, CDC1 ₃₎ δ 10.25 (s, IH), 8.09 (s, IH); 8.05 (d, 1H), 7.80 (d, 1H), 5.88 (s, 2H), 3.71 (t, 2H), 0.93 (t, 2H), 0.0 (s , 9H).

(Ii)

214

24.0 g (59.7 mmol) of 6-iodo-3-carboxaldehyde-1- [2- (trimethylsilanyl) ethoxymethyl] -4-indazole was dissolved in 350 mL of THF and cooled to 5 ° C. To this mixture was added 45.7 g (100 mmol, 1.68 eq) of solid 2-picolyltrienylphosphonium chloride / potassium hydride. The reaction mixture was allowed to stir for 45 minutes. To the mixture was added 20 mL of 3N HCl, followed by 50 mL of saturated aqueous sodium bicarbonate to pH 6. The excess THF was removed under reduced pressure and the residue was partitioned between ethyl acetate and water. The organic layers were washed with saturated aqueous sodium bicarbonate, water, and the organic layer was separated, dried over sodium sulfate, decanted and concentrated under reduced pressure. The residue was taken up in 1: 9 ethyl acetate: hexane and filtered. The filtrate was purified by silica gel chromatography (2 L silica gel, 20 to 30 to 50% ethyl acetate / hexane) to give 18.9 g (66% yield) of 6-iodo-3-E- [2- (pyridin-2-yl)]. ) ethenyl-1- [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole: R _f 0.52, p 0.25 (ethyl acetate / hexane 2: 8), ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.64 (m,

1H), 8.00 (d, 1H, J = 0.7Hz), 7.87 (d, 1H, J = 16.4Hz), 7.80 (d, 1H, J = 8.5Hz) 7.69 (td, 1H, J = 7.7, 1.8 Hz), 7.55 (d, 1H, J = 16.4 Hz), 7.55 (dd, 1H, J = 8.5) 1.3 Hz), 7.47 (d, 1H, J = 7.9 Hz), 7.18 (dd, 1H, J = 1.1, 4.8 Hz), 5.70 (s, 2H )

3.59 (t, 2H, J = 8.2 Hz), 0.90 (t, 2H> J = 8.2 Hz), -0.04 (s, 9H), ¹³ C NMR (75 MHz, CDCl 3) ) δ 156, 8, 151.2, 144.2, 143.6,

138.0, 132, 3, 132.2, 124.4, 124, 0, 123, 8, 123.7, 123, 5, 120, 7, 94, 1, 79, 4, 68, 1, 19, 17, 0, 0.

215 (iii)

In a 200 mL round bottom flask, 13.7 g (41.9 mmol, 2.5 eq) of cesium carbonate was weighed and dried under high vacuum and heated with a hot air gun. Then, 1.37 g (1.68 mmol, 0.1 eq) of the catalyst [Pd (dppf) Cl ₂ -CH ₂ Cl ₂ ] and 8.0 g (16.76 mmol) of 6-iodo-3E- [ 2- (pyridin-2-yl) ethenyl-1- [2- (trimethylsilanyl) ethoxymethyl] ind-indazole was taken up in 71 mL DMF. To this mixture was added 4.62 mL (33.5 mmol, 2.0 eq) of methylthiosalicylate and the vessel was heated at 85 ° C for 4.5 hours. The mixture was cooled to 23 ° C, partitioned between 350 mL ethyl acetate and 300 mL 50% saturated aqueous sodium bicarbonate. The organic layers were washed with 200 mL of 10% sodium bisulfite, brine and the organic layer was separated. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (500 mL silica gel, 30-40-50% ethyl acetate-hexane) gave 6.44 g (74%) of 6 - [(2-methoxycarbonylphenyl) sulfanyl] -3-E- [2- (pyridine-2- yl) ethenyl] -1 [2- (trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole: R _f 0.52, p 0.19 (ethyl acetate: hexane 3: 7), FTIR (thin film) 2950, 2887, 2356 , 1713, 1585, 1464, 1433, 1250, 1076, 837 cm ^{-1, Τ Η} NMR (300

MHz, CDC1 ₃₎ δ 8.70 (D, 1H), 8.12 (D, 1H), 8.04 (d, 1H), 7, 99 (d, 1H, J = 16) 4 Hz), 7 90 (s, 1 H), , 7, 88 (t, 1 H), 7.76 (d, 1H, J = 16.4 Hz) 7, 62 (D, 1H), 7.55 (D, 1H), 7.30-7.15 (m, 3H), 6.92 (d, IH); 5, 80 (with, 2H), 4.01 (with, 3H), 3.78 (t, 2H), 0, 96 (t, 2H), -0.03 (with, 9H), ¹³ C NMR (75 MHz, CDCl3) δ 168.3, 156.8, 151.2, 144.3, 144, 2 , 143.2, 138.0, 133 , 8, 133, 6, 132.5, 132.4,

216

129, 9, 129, 3, 128.5, 126, 0, 124, 7, 124, 6, 123, 8, 123, 5, 118, 3

79, 4, 68.2, 53.7, 19.2, 0.0, LCMS (100% area) Rt = 4.4 min (pos) [M + H] / z calcd 518.2, measured 518, second

(Iv)

To 8.50 g (16.4 mmol) of 6 - [(2-methoxycarbonylphenyl) sulfanyl) 3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethylsilanyl) ethoxymethyl] -1H 120 ml of THF, 120 ml of methanol, 120 ml of water and 15.9 g (115 mmol, 7.0 eq.) of potassium carbonate were added to the indazole. The mixture was heated to 67 ° C and stirred for 22 hours. The mixture was cooled and excess solvent was removed. The residue was partitioned between 300 mL of ethyl acetate and 250 mL of water. The aqueous layer was acidified with 20% citric acid to pH 5 (~ 70 mL) and the aqueous layer was drained.

The organic layer was washed with 50 mL of water and 100 mL of hexane was added to aid precipitation of the crystals formed in the ethyl acetate layer. The solid was filtered and dried to give 7.56 g (91%) of 6 - [(2-carboxyphenyl) sulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- ( trimethylsilanyl) ethoxymethyl] -ΙΗ-indazole: R _f 0.67, p 0.41 (mixture of ethyl acetate and

hexane to nu 8: 2) ^X H NMR (300 MHz, CDC1 ₃₎ δ 8.60 (m, 1H), 8.10 (D, 1H, J = 8.4 8.04 (dd, 1H, J = 1.7, 7.7 Hz) , 7.8 5 (d, 1H, J = 16.5 Hz 7.83 (s, 1H); 7.70 (dt, 1H, J = 1.7. 7.7 Hz), 7, 59 (d, 1 H, J = 16.5 Hz), 7.52 (d, 1H, J = 7.9) Hz), 7, 38 (Dd, 1H, J = 1.3 (8.4 Hz), 7.22-7.10 (m, 3H), 6.80 (Dd, 1H, J = 1.0. 8.0 Hz) 3.59 (t, 2H, J = 8.1 Hz), 0.85 (t , 2H, J = 8.81 Hz), -0.1 (S, , 9H).

217 (v)

820 mg (1.63 mmol) of 6 - [(2-carboxyphenyl) sulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole was dissolved in 5 ml DMF and treated

4.1 mL (8.13 mmol, 50 eq) of methylamine (2M in THF and 929 mg (2.44 mmol, 1.5 eq) of HATU) was stirred for 30 min, partitioned between ethyl acetate and saturated aqueous sodium bicarbonate and the organic layer was separated, dried over sodium sulfate, decanted and concentrated under reduced pressure Purification by silica gel chromatography (50 mL silica gel, 60-70% ethyl acetate / hexane) gave 795 mg (94%) 6- [2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1- [2- (trimethylsilanyl) ethoxymethyl] -4-indazole as a solid: Rf sm 0.35 , p 0.23 (6: 4 ethyl acetate / hexane), FTIR (thin film) 3306, 2951, 1643, 1606, 1587, 1563, 1469, 1433, 1410,

1303, 1249, 1217, 836 cm ^-1 , ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.70 (m, 1H), 8.06 (d, 1H, J) = 8.4 Hz), 7.94 (d, 1H, J = 16.3 Hz), 7.74 (dt, 1 H, J = 1.8, 7.7 Hz), 7.70-7, 60 (m, 3H); 7.52 (D, 1H, J = 7.9 Hz), 7.35-7 , 20 (m, 5H), 6.45 (bs, 1H), 5, 80 (with, 2H), 3.62 (t, 2H), 3.00 (d, 3H), 0.93 (t, 2H); -0, 05 (with, 9H),

¹³ C NMR (75 MHz, CDCl ₃ )? 179.7, 169, 9, 156, 8, 151, 1, 144.2, 143, 0, 138, 1, 136, 1, 135, 4, 133.2 , 132.2, 132.1, 130, 2, 128, 5,

127.2, 124.7, 124, 1, 123.8, 123, 5, 123, 3, 114, 9, 68.1, 28.2,

19.2, 0.00, LCMS (100% region) R t = 4.15 min (pos) [M + H] / z calcd 517.2, measured 517.2.

218

Example 33 (b)

6- [2- (2-methyl-quinolin-6-ylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 33 (b) was prepared in a similar manner to that described in Example 33 (a) except that in step (v), 6-amino-2-methylquinoline was used in place of methylamine: ³ H NMR (300 MHz, CDC1 ₃₎ δ 10.2 (br s, 1H), 8.64 (m, 1H), 8.40 (s, 1H), 8.23 (s, 1H), 7.98 to 7, 80 (m 4H), 7.69 (dt, 1H, J = 1.7, 7.7 Hz), 7.55-7.40 (m, 7H), 7.25-7.16 (m, 3H),

2.71 (s, 3H).

Example 33 (c)

6- [2- (phenylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 33 (c) was prepared in a similar manner to that described in Example 33 (a) except that in step (v), aniline was used instead of methylamine: ¹ H NMR (300 MHz, DMSO-d 6) δ 13 35 (s, 1 H), 10.53 (s, 1 H), 8.67 (m, 1 H), 8.22 (d, 1 H, J = 7.5 Hz), 7.99 (d, 1 H, J = 16.4 Hz), 7.85 (dt, 1H, J = 1.8, 7.6 Hz), 7.8-7.55 (m, 5H), 7.45-7.10 (m .

219

9Η), LCMS (100% area) R t = 3.86, (pos) [M + H] / z calcd

449.1, measured 449.1. Analyzed with 0.41 H ₂ O, calculated: C (71.13), H (4.60), N (12.29), S (7.03). Found: C (71.04), H (4.62), N (12.31), S (7.01).

Example 33 (d)

6- [2- (3-chlorophenylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

Example 33 (d) was prepared in a similar manner to that described in Example 33 (a) except that in step (v), 3-chloroaniline was used in place of methylamine: NMR (300 MHz, CDCl ₃ ) δ 8, 53 (m, 1H), 7.92 (d, 1H, J = 8.4Hz),

7.77 (d, 1H, J = 16.4 Hz), 7.68 (dt, 1H, J = 1.7, 7.7 Hz), 7.64-7.56 (m, 2H), 7 51-7.43 (m, 3H); 7.35-7.28 (m, 4H);

7.12 (m, 3H), 7.02 (m, 1H), LCMS (100% area) Rt 3.98 min (pos) [M + H] / z calcd 483.1, found 483.1. Analyzed with 0.3 H2O, calculated: C (66, 40), H (4.05), N (11.47), S (6.57). Found: C (66.36), H (4.08), N (11.49), S (6.55).

Example 33 (e)

6- [2- (cyclopropylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

220

Example 33 (e) was prepared in a similar manner to that described in Example 33 (a) except that in step (v), cyclopropylamine was used instead of methylamine ^: 1 H NMR (300 MHz, DMSO-d ₆ ) δ 13.45 (s, 1H), 8.73 (d, 1H, J = 3.9 Hz), 8.56 (d, 1H, J = 4.3 Hz), 8.31 (d, 1H, J = 8.5 Hz), 8.08 (d, 1H, J = 16.4 Hz), 7.91 (dt, 1H, J = 1.7, 7.7 Hz), 7.78 (d, 1H J = 7.8 Hz), 7.70 (m, 2H), 7.57 (m, 1H), 7.40 (m, 3H),

7.30 (d, 1H, J = 8.4Hz), 7.20 (d, 1H, J = 7.8Hz), 2.94 (m, 1H), 0.80 (m, 2H), 0.65 (m, 2H), LCMS (100% area) Rt 3.51 min (pos) [M + H] / z calcd 413.1, found 413.1.

Example 33 (f)

6- [2- (2,2,2-Trifluoroethylcarbamoyl) phenylsulfanyl] -3-E- [2-pyridin-2-yl) ethenyl] -1H-indazole

Example 33 (f) was prepared in a similar manner to that described in Example 33 (a) except that in step (v), 2,2,2-trifluoroethylamine was used in place of methylamine: ^lam NMR (300 MHz, DMSO-d ₆₎ δ 13.5 (s, 1H), 9.29 (t,

1H, J = 6.3Hz), 8.74 (m, 1H), 8.37 (d, 1H, J = 8.3Hz), 8.10 (d, 1H, J = 16.4Hz) 7.94 (dt, 1H, J = 1.8, 7.6 Hz), 7.80 (d,

221

1 H, J = 7.9 Hz), 7.75-7.65 (m, 3H), 7.55-7, 40 (m, 3H), 7.33 (d, 1H), 7.22 (d , 1H), 4.22 (m, 2H), LCMS (100% area) Rt =

3.70 minutes (pos) [M + H] / z calc 455.1, measured 455.1.

Example 33 (g)

Of tetrabutylammonium 6- [2- (carboxy) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 33 (g) was prepared in a similar manner to that described in Example 33 (a) except that step (v) was omitted: R f sm 0.41, p 0.0 (8: 2 ethyl acetate-hexane) ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 8.75 (m, 1H), 8.25 (d, 1H, J = 8.6 Hz), 8.05 (d, 1H, 16, 4 Hz), 7.88 (dt, 1H, J = 1.8,

7.8 Hz), 7.83-7, 60 (m, 4H), 7.33 (m, 2H), 7.16 (m, 2H), 6.70 (m, 1H), 3.30 ( m, 8H), 1.70 (m, 8H), 1.42 (m, 8H), 1.05 (t, 12H), LCMS (100% region) Rt 3.24 (pos) [M + H ( acid component only)] / z calculated 374.1, measured 374.1. Analyzed with 0.1 H ₂ O, calculated: C (72.07), H (8.21), N (9.09), S (5.20). Found: C (72.04), H (8.29), N (9.06), S (5.12).

Example 33 (h)

6- [2- (3-Chloro-phenylcarbamoyl) phenylsulfanyl] -3-Z- [2- (pyridin-2-yl) ethenyl] -lH-indazole

222

The

Example 33 (h) was prepared by the same reaction as Example 33 (d). It should be noted that although this compound was isolated and characterized as pure, it was found to form the isomer of Example 33 (d) under assay conditions. ^X H NMR (300 MHz, CDC1 ₃₎ δ 8.82 (m, 1 H);

8.31 (s, 1H), 7.86 (m, 2H), 7.77 (m, 2H), 7.61 (t, 1H, J = 2.0 Hz), 7.46 (d, 1H) J = 8.0 Hz), 7.33 (m, 5H), 7.21 (t, 1H, J = 8.0 Hz), 7.13 (dd, 1H, J = 1.5, 8, 1 Hz), 7.08 (m, 1H), 6.98 (d, 1H, J = 13.0 Hz), 6.66 (d, 1H, J = 13.1 Hz), LCMS (100% area) R t 4.40 min (pos) (M + H] / z calcd 483.1, measured 483.1. Analyzed with 0.3 H ₂ O, calcd: C (66, 40), H (4.05) N (11.47), S (6.57) Found: C (66, 36), H (4.08), N (11.49), S (6.55).

Example 34

6- [2 - ((RS- (trans -2-phenylcyclopropyl) carbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 33 (g) was converted to Example 34 in a similar manner to that described in Example 33 (a), step (v) except that trans-2-phenylcyclopropylamine was used in place of methylamine: FTIR (thin film) 1704, 1638, 1584, 1559, 1530, 1497, 1460, 1430, 1339, 1306, 1269, 1223,

1152, 1086, 1061, 966, 844 cm ^"1; H NMR (300 MHz, CDC1 ₃₎ δ 13.3

223

(WITH, 1H), 8.71 (d, 1H, J = 4.4Hz); 8.61 (d, 1H, J) = 3.9 Hz), 8.20 (D, 1H, J = 8.5Hz), 7.96 (d, 1H, J = 16.4Hz) , 7.81 (Dt, 1H, J = 1.7, 7.6 Hz), 7.66 (d, 1H, J = 7.8 Hz), 7, 59 to 7.50 (M,

3Η), 7.37-7.25 (m, 5H), 7.21-7.08 (m, 5H), 3.01 (m, 1H), 2.03 (m, 1H), 1.25 (m, 2H), LCMS (100% area) R t = 3.72 minutes (pos) [M + H] / z calcd 489.2, measured 489.2. Analyzed with 0.6 MeOH, 0.16 CH 2 Cl 2 calculated: C (70, 86), H (5.17), N (10.75), S (6.15) .Namer: C (70.87), H (5.18), N (10.75), S (5.96).

Example 35 (a)

6- [2- (N-propylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

mg (0.1112 mmol) of 6- [2- (pentafluorophenoxycarbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -4-indazole was dissolved in 0.8 ml DMF treated with 11 μΐ (0.1335 mmol) of n-propylamine and stirred at room temperature. HPLC analysis after 15 minutes showed that all starting material was consumed. The reaction mixture was concentrated on a rotary evaporator under high vacuum to give a solid. The solid was sonicated with CH ₂ Cl ₂ to give a fine suspension, which was filtered and washed with CH ₂ Cl ₂ to give 40 mg (87% yield) of the title compound. ¹ H NMR (DMSO-d 6) δ 13.31 (s, 1H),

8.60 (d, J = 4.0 Hz, 1H); 8.41 (t, J = 6.2 Hz, 1H); 8.19 (d, J = 8.5 Hz, 1H); 94 (m, 3H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H),

7.66 (t, J 8.7 Hz, 1H), 7.56 (m, 2H), 7.47 (m, 1H), 7.30 (m, 3H), 7.18 (d, T = 8.3 Hz, 1H), 3.20 (q, J = 6.0 Hz, 2H), 1.55

224 (septet, J = 5.9 Hz, 2H), 0.92 (t, J = 6.0 Hz, 3H). Anal, calcd for C 24 H ₂₂ N 4 OS · (1.5 H ₂ O, 0.8 DMF): C, 63.41, H, 6.17, N, 13.45, S, 6.41. Found: C, 63.37, H, 5.68, N, 13.44, S, 6.32.

The starting material was prepared as follows:

A solution of 615 mg (1.0 mmol) of tetrabutylammonium-6- (2-carboxyphenylsulfanyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole dissolved in 10.0 ml of dry DMF was treated with 89 μΐ (1.1 mmol) of pyridine and 206 μΐ (1.2 eq.) Of pentafluorophenyltrifluoroacetate, at room temperature, under an argon atmosphere. HPLC analysis after 45 minutes showed mainly unreacted carboxylic acid, so an additional 89 μΐ (1.1 mmol) of pyridine and 206 μΐ (1.2 eq) of pentafluorophenyltrifluoroacetate were added. HPLC analysis 15 minutes later showed that the starting acid was fully consumed. The reaction mixture was concentrated under high vacuum on a rotary evaporator, then triturated with CH 2 Cl 2 (H mL), causing crystals to form which were collected by filtration, washed with additional CH ₂ Cl ₂ and dried. The weight of the bright yellow crystals was 336 mg. The remaining filtrate was concentrated and purified by flash chromatography (10% acetonitrile / CH 2 Cl 2 to 80% acetonitrile / CH 2 Cl 2) to give an additional 70 mg of solid. The overall yield of 6- [2- (pentafluorophenoxycarbonyl) phenylsulfanyl] 3-E- [2- (pyridin-2-yl) ethenyl] -4-indazole was 406 mg or 89%. ^X H NMR (CDCl3) δ 10.22 (1H, bs), 8.66 (1H, d, J = 4.5

Hz), 8.28 (2H, dd, J = 7.7, 1.5 Hz), 8.15 (1H, d, J = 8.5 Hz),

225

7.97 (1H, d, J = 16.2 Hz), 7.79 (1H, s), 7.15-7.75 (7H, m),

6.92 (1H, d, J = 8.1Hz).

Example 35 (b)

6- [2- (i-Propylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl-1H-indazole

Example 35 (b) was prepared in a similar manner to that described in Example 35 (a) except that isopropylamine was used in place of n-propylamine. ^X H NMR (DMSO-de) δ 13.30 (s, 1H), 8.60 (d, J = 4.5 Hz, 1H), 8.26 (d, J = 7.34 Hz, 1 H); 8.19 (d, J = 8.3 Hz, 1H), 7.94 (d, J = 16.4 Hz, 1H), 7.80 (dt, J = 1.7, 7.5 Hz, 1H) ), 7.66 (d, J = 7.7Hz,

1H), 7.56 (m, 2H), 7.45 (m, 1H), 7.30 (m, 3H), 7.18 (d, J =

8.5 Hz, 1H), 7.08 (m, 1H), 4.04 (septet, J = 7.4 Hz, 1H), 1.15 (d, J = 6.6 Hz, 6H). Anal. Calcd for C ₂₄ H ₂ N ₄ OS · 1.7 H ₂ O: C, 64.75, H, 5.75, N, 12.59, S, 7.20. Found: C, 64.79, H, 5.36, N, 12.74, S, 7.08.

Example 35 (c)

6- [2- (Cyclobutylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

226

The compound of Example 35 (c) was prepared in a similar manner to that described in Example 35 (a) except that cyclobutylamine was used in place of n-propylamine. ^X H NMR (DMSO-d ₆₎ δ 13.31 (s, IH), 8.62 (m, 2H), 8.19 (d, J = 8.5 Hz,

1H), 7.94 (m, 2H), 7.80 (dt = 1.7, 7.5 Hz, 1H), 7.65 (t, J =

8.1 Hz, 1H), 7.56 (s, 1H), 7.47 (m, 1H), 7.30 (m, 3H), 7.17 (d, J = 8.3 Hz, 1H) 4.36 (septet, J = 8.1 Hz, 1H), 2.22 (m, 2H), 2.03 (m, 2H), 1.67 (m, 2H). Anal. Calcd for C 25 H ₂₂ N 4 OS · (0.5 H ₂ O, 0.9 DMF): C, 66, 36, H, 5.89, N, 13.69, S, 6.40.

Found: C, 66.21, H, 5.78, N, 13.82, S, 6.36.

Example 35 (d)

6- (2-karbamoylfenylsulfanyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1Hindazol

The compound of Example 35 (d) was prepared in a similar manner to that described in Example 35 (a) except that ammonia was used in place of n-propylamine. ^X H NMR (DMSO-d ₆₎ δ

8.60 (d, J = 4.9 Hz, 1H), 8.21 (d, J = 8.3 Hz, 1H), 7.94 (m,

3H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7.60 (m, 4H), 7.48 (bs,

1H), 7.25 (m, 4H), 7.0 (m, 1H). Tknal. Calculation for C21H16N4OS ·

0.25 _H2O: C, 66.91, H, 4.41, N, 14.86, S, 8.51. Measured: C,

66, 99, H, 4.40, N, 15.10, S, 8.49.

227

Example 35 (e)

6- [2 - ((l-methylpyrrole-2-ylhydrazido) carbonyl) phenylsulfanyl] -3-E [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 35 (e) was prepared in a similar manner to that described in Example 35 (a) except that 1-methylpyrol-2-ylhydrazide was used in place of n-propylamine. ^X H NMR (DMSO-d ₆₎ δ 13.34 (s, IH), 10.25 (s, IH), 10.45 (s, IH);

8.60 (d, J = 4.5 Hz, 1H), 8.22 (d, J = 8.7 Hz, IH), 7.95 (d, J = 16.2 Hz, IH), 7, 81 (dt, J = 1.7, 7.5 Hz, 1H), 7.66 (m, 3H),

7.57 (d, J = 16.0 Hz, 1H), 7.43-7.18 (m, 4H), 7.07 (d, J = 7.9 Hz, 1H), 7.00 (d J = 3.4 Hz, 2H), 6.07 (t, J = 3.2 Hz, 1H),

3.88 (s, 3H). Anal. Calcd for C 27 H 22 N ₆ O ₂ S · 0.6 H ₂ O: C, 64.17, H, 4.63, N, 16.63, S, 6.34. Found: C, 64.24, H, 4.48, N, 16.56, S, 6.28.

Example 35 (f)

6- [2 - ((2-fluorobenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2 (pyridin-2-yl) ethenyl] -1H-indazole

Example compound

35 (f) was prepared in a manner similar to that described in Example 35 (a) except that

2-Fluorobenzylamine was used instead of n-propylamine. ¹ H NMR

228 (DMSO-d 6) δ 13.31 (s, 1H), 8.99 (t, J = 5.8 Hz, 1H), 8.61 (d, J = 4.5 Hz, 1H), 19 (d, J = 8.5 Hz, 1H), 7.94 (d, J = 16.2 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7.66 (d, J = 8.1 Hz, 1H), 7.56 (m, 3H), 7.47 (t, J = 7.9 Hz, 1H), 7.31 (m, 4H), 7.15 (m, 4H), 4.51 (d, J = 5.7 Hz, 2H). Anal. Calcd for C ₂₈ H ₂₁ FN ₄ OS · 0.25 H ₂ O: C, 69, 33, H, 4.47, N, 11.55, S, 6.61. Found: C, 69.32, H, 4.41, N, 11.58, S, 6.59.

Example 35 (g)

6- [2 - ((4-methoxybenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2 (pyridin-2-yl) ethenyl] -1H-indazole

Example 35 (g) was prepared in a similar manner to that described in Example 35 (a) except that

4-methoxybenzylamine was used instead of n-propylamine. ¹ H NMR (DMSO-d 6) δ 13.31 (s, 1H), 8.90 (t, J = 5.5 Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H), 8.19 (d, J = 83Hz, 1H), 7.95 (d, J = 16.3Hz, 1H), 7.81 (dt, J = 1.7, 7.5Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7.55 (m, 3H), 7.30 (m, 5H), 7.18 (d, J = 8.5 Hz, 1H), 7.10 (d, J = 8.3 Hz, 1H), 4.39 (d, J = 6.0 Hz, 2H), 3.72 (s, 3H). Anal. Calcd for C ₂₉ H ₂₄ N ₄ O ₂ S · 0.6 H ₂ O: C, 69.19, H, 5.05, N, 11.13, S, 6.37. Found: C, 69.12; H, 4.85; N, 11.24; S, 6.35.

Example 35 (h)

6- [2 - ((5-methylfur-2-yl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

The compound of Example 35 (h) was prepared in a similar manner to that described in Example 35 (a) except that

5-Methylfur-2-ylamine was used in place of n-propylamine. ¹ H NMR (DMSO-d 6) δ 13.31 (s, 1H), 8.88 (t, J = 5.3 Hz, 1H), 8.60 (d, J

229

= 4.3 Hz, 1H), 8.19 (d, J = 8.3) Hz, 1H), 7.95 (d, J = 16.3 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7 66 (d, J = 8.1 Hz, 1H), 7.54 (m, 3H), 7.30 (m, 4H); 7.18 (d, J = 8.3 Hz, 1H) 7, 06 (D,

J = 8.1 Hz, 3H). Anal. Calc., For C 27 H 22 N 4 O ₂ S · 0.4 H ₂ O: C,

68, 45, H, 4.85, N, 11.83, S, 6.77. Found: C, 68.35, H, 4.80, N, 11.85, S, 6.68.

Example 35 (i)

6- [2- (Benzyloxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 35 (i) was prepared in a similar manner to that described in Example 35 (a) except that O-benzylhydroxylamine was used in place of n-propylamine. ¹ H NMR

(DMSO-d 6) δ 13.31 (with, 1H), 11.64 (s, 1H), 8.90 (t, J = 5.5 Hz, 1H), 8.60 (d, J = = 4.1 Hz, 1H), 8.19 (D, J = 8.3 Hz (1H), 7.95 (d, J = 16.3Hz, 1H), 7, 81 (dt, J = 1.7. 7.5 Hz (1H); 7.66 (d, J = 7.9 Hz, 1H), 7, 56 (M, 2H), 7.50- • 7.24 (m, 9H), 7.17 (t, J =

8.5 Hz, 2H), 4.94 (s, 2H). Anal. Calcd. For C28H22N4O2S · 0.8

230

H ₂ O: C, 68.22, Η, 4.83, N, 11.37, S, 6.50. Found: C, 68.08, H, 4.65, N, 11.41, S, 6.47.

Example 35 (j)

6- [2- (allyloxykarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 35 (j) was prepared in a similar manner to that described in Example 35 (a) except that O-allyl hydroxylamine was used in place of n-propylamine. ¹ H NMR (DMSO-d 6) δ 13.32 (s, 1H), 11.56 (s, 1H), 8.60 (d, J = 4.1 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.95 (d, J = 16.5 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7.66 (d J = 7.9 Hz (1H), 7.56 (m, 2H), 7.48-7.24 (m, 5H), 7.16 (m, 2H), 6.00 (m, 1H) 5.37 (d, J = 18.3 Hz, 1 H), 5.27 (d, J = 11.3 Hz, 1 H), 4.42 (d, J = 6.0)

Hz, 1H). Anal. Calculation for C ₂₄ H ₂₀ N ₄ O ₂ S · (0.2 H ₂ O, 0.2 CH ₂ Cl ₂ : C, 65, 35, H, 4.96, N, 12.10, S, Found: C, 65.24; H, 4.50; N, 12.56; S, 7.17.

Example 35 (k)

6- [2- (izopropoxykarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

231

The compound of Example 35 (k) was prepared in a similar manner to that described in Example 35 (a) except that O-isopropylhydroxylamine was used instead of n-propylamine. ¹ H

NMR (DMSO-d 6) δ 13.30 (s, 1H), 11.33 (s, 1H), 8.60 (d, J = 4.1 Hz, 1H), 8.19 (d, J 8, 3 Hz, 1H), 7.95 (d, J = 16.5 Hz, 1H),

7.81 (dt, J = 1.7, 7.5 Hz, 11.76 (d, J = 7.9 Hz, 1H), 7.55 (m, 2H), 7.48-7, 24 (m, 4H), 7.17 (d, J = 8.3 Hz, 2H), 4.12 (septet, J = 5.7 Hz, 1H), 1.21 (d, J = 6.2) Hz, 6H Anal, Calcd for C24H22N4O2S · (0.4 H ₂ O, 0.7 CH ₂ Cl ₂ ): C, 59, 67, H,

4.91, N, 11.27, S, 6.45. Found: C, 59.61, H, 4.81, N,

11.42, S, 6.45.

Example 35 (1)

6- [2 - ((4-aminobenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 35 (1) was prepared in a similar manner to that described in Example 35 (a) except that 4-aminobenzylamine was used in place of n-propylamine. ¹ H NMR (DMSO-d ₆ ) δ 13.31 (s,

1H), 8.78 (T, J = 6.0 Hz, 1 H), 8, 60 (d, J = 4.3 Hz, 1 H), 8.19 (D, J = 8.1 Hz, 1H), 7.95 (D, J = 16.3 Hz, 1H), 7.85 (bs, 1H), 7, 81 (dt J = 1.7, 7.5 Hz, 1H), 7.66 (d, J = 7.9Hz, 1H), 7.59 (with, 1H), 7.51 (m, 2H). 7.30 (m, 3H), 7.19 (d, J = 8.7 Hz, 1H), 7, 05 (M, 3H), 6.56 (d, J = 8.7 Hz, 1H), 6.51 (d, J = 8.5)

Hz, 2H), 4.29 (d, J = 6 > 0 Hz, 2H). Anal. Calcd. For C 28 H 23 N 5 OS

232 • 0.6 H ₂ O: C, 68, 86, Η, 4.99, N, 14.34, S, 6.57. Found: C, 68.83, H, 4.80, N, 14.16, S, 6.52.

Example 35 (m)

6- [2 - ((thien-2-ylhydrazido) carbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 35 (m) was prepared in a similar manner to that described in Example 35 (a) except that thien-2-ylhydrazide was used in place of n-propylamine. ^X H NMR (DMSO-de) δ 13.49 (br s, 1H), 10.64 (s, 1H), 10.47 (s, 1H), 8.66 (d, J = 4.0 Hz, 1H, 8.22 (d, J = 85Hz, 1H), 8.08-7.82 (m, 5H), 7.66 (m, 3H), 7.39 (m, 3H), 7.24 (m, 2H), 7.09 (d, J =

8.1 Hz, 1H), 7.00 (d, J = 3.4 Hz, 2H), 6.07 (t, J = 3.2 Hz, 1H), 3.88 (s, 3H). Anal. Calcd for C 26 H ₁₉ N ₅ O ₂ S · 1.5 H ₂ O: C, 59.52, H, 4.23, N, 13.35, S, 12.22. Found: C, 59.56, H,

4.42, N, 13.33, S, 11.75.

Example 35 (n)

6- [2- (N ² - (pyrid-2-ylhydrazino) carbonyl) phenylsulfanyl] -3-E- [2 (pyridin-2-yl) ethenyl) -1H-indazole

233

Example 35 (n) was prepared in a similar manner to that described in Example 35 (a) except that

2-Hydrazinopyridine was used instead of n-propylamine. ^X H NMR (DMSO) δ 1'3,31 (s, 1H), 10.30 (s, 1H), 8.60 (d, J = 4.4 Hz,

1H), 8.48 (s, 1H), 8.21 (d, J = 8.5Hz, 1H), 8.09 (d, J = 4.9Hz, 1H), 7.94 (d, J = 16.4 Hz, 1H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7.67 (m, 1H), 7.62-7.47 (m, 3H) 7.40 (m, 2H), 7.31 7.12 (m, 3H), 6.73 (m, 2H). Anal. Calculation for C ₂₆ H ₂₀ NeOS · 0.3 H ₂ O:

C, 66.45, H, 4.42, N, 17.88, S, 6.82. Found: C, 66.33, H, 4.50, N, 17.78, S, 6.60.

Example 35 (o)

6- [2- (N-hydroxy-N-methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

from Example 35 (o)

The compound was prepared in a similar manner to that described in Example 35 (a) except that

N-methylhydroxylamine was used instead of n-propylamine. ¹ H NMR

(DMSO-de) δ 13,24 (with, 1H), 9.94 (s, 1H); 8.60 (d J = 4.0 Hz 1H), 8.14 (d, J = 8.3 Hz, 1H) 7.92 (d, J = 16.2) Hz, 1H), 7.80 (dt, J = 1.7, 7.5 Hz, 1H), 7.65 (t, J = 8.5Hz, 1H), 7.54 (d, J = 16.5 Hz, 1H) 7.47 -7.24 (m, 6H), 7.16 (d, J = - 8.5 Hz, 1H) 3.24 (b s, 1H). Anal. computing for C ₂₂ HigN ₄ O ₂ S · (0.5 H ₂ O, 0.3 CH ₂ C1 ₂ ): C, 61.29, H, 4.52, N, 12.82, S, 7.34. Measured: C,

H, 4.33; N, 12.67; S, 7.34.

Example 35 (p)

234

6- [2 - ((pyrid-4-yl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 35 (p) was prepared in a similar manner to that described in Example 35 (a) except that

4-Aminomethylpyridine was used instead n-propylamine. ¹ H NMR (DMSO-d 6) δ 13.31 (š s, 1H), 9.07 (t, J = 6.8 Hz, 1H), 8.60 (D, J = 4.2 Hz, 1H) 8.48 (d, J = 5.0Hz, 1H), 8.19 (d, J = 8.7 Hz, 1H), 7.95 (d, J = 1 6.4 Hz (1H), 7.70 (dt, J = 1.7, 7.5 Hz, 1H), 7.68-7.52 (m, , 3H), 7.42 (m, 2H); 39-7.31 (m, 3H). 7.27

(m, 1H), 7.20 7.10 (m, 2H), 4.48 (d, J = 6.2 Hz, 2H).

Example 35 (q)

6- [2 - ((2-metylfenylhydrazido) carbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 35 (q) was prepared in a similar manner to that described in Example 35 (a) except that

2-Methylphenylhydrazide was used in place of n-propylamine. ¹ H NMR (DMSO-d 6) δ 13.43 (br s, 1H), 10.45 (s, 1H), 10.28 (s, 1H), 8.64 (d, J = 4.0 Hz, 1H), 8.22 (d, J = 8.2 H2, 1H), 8.01 (d, J =

16.6 Hz, 1H), 7.92 (m, 1H), 7.81 (m, 1H), 7.69 (m, 1H), 7.60

235 (d, J = 16.4 Hz, 1 H), 7, 50-7.22 (m, 8H), 7.07 (d, J = 7.7 Hz,

1H), 2.45 (s, 3H).

Example 35 (r)

6- [2- (methoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

Example 35 (r) was prepared in a similar manner to that described in Example 35 (a) except that O-methylhydroxylamine was used in place of n-propylamine. ¹ H NMR

(DMSO -d ₆ ) δ 13,32 (with, 1H), 11.60 (s, 1H), 8.60 (d , J = 3.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 16.2 Hz, 1H), 7.81 (Dt, J = 1.7, 7.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H), 7, 56 (M, 2H), 7.47 (dd, J = 7, (1.7 Hz, 1H) , 7.43-7.24 (M, 3H), 7.17

(m, 2H), 3.72 (s, 3H). Anal. Calcd. For C22H18N4O2S · 0.6

CH ₂ Cl ₂ : C, 59.86, H, 4.27, N, 12.36, S, 7.07. Found: C, 59.94, H, 4.40, N, 12.00, S, 6.80.

Example 35 (s)

6- [2 - ((Cyclopropyl) methoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

236

The compound of Example 35 (s) was prepared in a similar manner to that described in Example 35 (a) except that O-cyclopropylhydroxylamine was used in place of n-propylamine. ¹ H NMR (DMSO-d ₆ ) δ 13.38 (s, 1H), 11.51 (s, 1H), 8.64 (d, J =

3.8 Hz, 1H), 8.18 (d, J = 8.4 Hz, 1H), 8.00 (d, J = 16.4 Hz,

1H), 7.86 (m, 2H), 7.63-7.52 (m, 2H), 7.49-7.29 (m, 4H), 7.17 (m, 2H), 3.70 (d, J = 7.2 Hz, 1 H), 1.10 (m, 1 H), 0.53 (m, 2 H),

0.27 (m, 2 H). Anal. Calcd for C 25 H 22 N ₄ O ₂ S · 1.6 H ₂ O: C, 63.70, H, 5.39, N, 11.89, S, 6.80. Found: C, 63.58; H, 4.95; N, 11.71; S, 6.66.

Example 35 (t)

6- [2- (N-propoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 35 (t) was prepared in a similar manner to that described in Example 35 (a) except that N-propylhydroxylamine was used in place of n-propylamine. ¹ H NMR (DMSO-d 6) δ 13.31 (s, 1H), 11.48 (s, 1H), 8.60 (d, J = 3.8 Hz, 1H), 8.19 (d, J = 8.4 Hz, 1H), 7.95 (d, J = 16.2 Hz, 1H),

7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7.66 (d, J = 7.9 Hz, 1H),

7.62-7.52 (m, 2H), 7.49-7.24 (m, 4H), 7.17 (m, 2H), 3.84 (t, J = 6.6 Hz, 2H) 1.62 (septet, J = 6.4 Hz, 2H), 0.92 (t, J = 6.1

Hz, 3H). J \ nal. Calculation for C 24 H ₂₂ N ₄ O ₂ S (0.5 H ₂ O, 0.25 CH ₂ Cl ₂ ):

C, 63.21; H, 5.14; N, 12.16; S, 6.96. Found: C, 63.15, H, 5.13, N, 12.17, S, 6.99.

237

Example 35 (u)

6- [2- (allylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 35 (u) was prepared in a similar manner to that described in Example 35 (a) except that allylamine was used in place of n-propylamine. ^X H NMR (DMS0-d ₆₎ δ 13.31 (s, 1H), 8.60 (m, 2H), 8.19 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 16.3 Hz, 3H), 7.79 (dt, J = 1.7, 7.5 Hz, 1H), 7.64 (m, 1H, 7, 60-7.48 (m, 3H)) 7.37-7.23 (m, 3H), 7.17 (d, J = 8.5 Hz, 1H), 7.07 (m, 1H), 5.87 (m, 1H), 5, 25 (dq, J = 17.33, 1.9 Hz, 1H), 5.09 (dq, J = 10.2, 1.9 Hz, 1H), 3.87 (m, 2H). for C ₂₄ H ₂₀ N ₄ OS · 0.8 CH ₂ Cl ₂ : C, 62.00, H, 4.53, N, 11.66, S, 6.67. N, 11.99; S, 6.66; MALDI FTMS (MH &lt; ^{+ &gt;} ) Calc .: 413.1431, found 413.1449.

Example 35 (v)

6- [2- (cyclopropylmethyl-) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 35 (v) was prepared in a similar manner to that described in Example 35 (a) except that cyclopropylmethylamine was used instead of n-propylamine. ¹ H NMR

238 _(DMSO-d6) δ 13.30 (s, ΙΗ), 8.60 (d, J = 4.0 Hz, 1H), 8.48 (t, J = 5.3 Hz, 1H), 8 17 (d, J = 8.7 Hz, 1 H), 7.90 (d, J = 16.4 Hz, 1 H), 7.80 (dt, J = 1.7, 7.5 Hz, 1 H) , 7.67-7.45 (m, 4H), 733-

7.23 (m, 3H), 7.18 (d, J = 83Hz, 1H), 7.06 (m, 1H), 3.13 (t, J = 6.2Hz, 2Ή), 1, 00 (m, 1 H), 0.41 (m, 1 H), 0.24 (m, 1 H). Anal. Calcd for C ₂₅ H ₂₂ N ₄ OS · 0.5 CH ₂ Cl ₂ : C, 65, 30, H, 4.94, N, 11.95, S, 6.84. Found: C, 65.10, H, 4.93, N, 12.04, S,

6.82. MALDI FTMS (MH ⁺ ) calc 427.1587, found 427.1605.

Example 35 (w)

6- [2- (cyanomethyl-carbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 35 (w) was prepared in a similar manner to that described in Example 35 (a) except that aminoacetonitrile was used in place of n-propylamine. ¹ H NMR

(DMSO-de) Δ 13.35 (s, 1H), 9.19 (t, J = 5.3 Hz, 1H), 8.60 (d, J) = 4.8 Hz, 1H), 8.20 (d, J = 8.7 Hz, 1H), 7.94 (d, J = 16.4 Hz, 3H), 7.79 (dt, J = 1.7) 7.5 Hz, 1H), 7.70-7.50 (m, 4H), 7,41- 7.23 (m, 3H), 7.18 (d, J = 8.5 HZ, 1H), 7.06 (d, J = 6.6 Hz, 1H), 4.32 (d, J = 5.5) Hz, 2H) . MALDI FTMS (MH ⁺ ) calculated 412.1227. measured 412.1215.

Example 35 (x)

6- [2- (ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

239

The compound of Example 35 (x) was prepared in a similar manner to that described in Example 35 (a) except that ethylamine was used instead of n-propylamine. ¹ H NMR (DMSO-d 6) δ

8.60 (d, J = 4.0 Hz, 1H); 8.40 (t, J = 6.2 Hz, 1H); 8.18 (d, J = 8.5 Hz, 1H); 94 (m, 3H), 7.81 (dt, J = 1.7, 7.5 Hz, 1H), 7.68-7.44 (m, 3H), 7.56 (m, 2H), 7 30 (m, 3H); 7.17 (dd, J =

8.1, 1.8 Hz, 1H), 7.06 (m, 1H), 3.24 (m, 2H), 1.11 (t, J = 7.0 Hz, 3H). Anal. Calcd. For C 23 H ₂₀ N 4 OS · (1.75 H ₂ O, 1.0 DMF): C,

H, 6.09; N, 13.87; S, 6.35. Found: C, 61.58, H, 5.66, N, 13.96, S, 5.93. MALDI FTMS (MH ⁺ ) calc 401, 1431, found 401.1417.

Example 35 (s)

6- [2- (thiazol-2-ylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 35 (y) was prepared in a similar manner to that described in Example 35 (a) except that

2-Aminothiazole was used in place of n-propylamine. ^X H NMR

(DMSO-de) δ 13,32 (s, 1H), 12.67 (with, 1H), 8.60 (d, J = 4.1Hz, 1H), 8.18 (D, J = 8.5 Hz, 1H), 7 93 (d, J = 16.3Hz, 1H), 7.80 (Dt, J = 1.7. 7.5 Hz, 1H) , 7.65 (D, J = 7.9 Hz, 1H), 7.65 (d, J = 8, 3 Hz, 1H), 7.60 to 7, 51 (m, 3H) , 7, 49-7, 34 m 2H), 7.26

240 (m, 2H); 7.18 (m, 2H). Anal. Calc'd for C ₂₄ H ₇ N ₅ OS ₂ · 0.75 H ₂ O: C, 61.45, H, 3.98, N, 14.93, S, 13.67. Found: C, 61.35, H, 4.10, N, 14.96, S, 13.68.

Example 35 (z)

6- [2- (2- (Ethoxy) ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 35 (z) was prepared in a similar manner to that described in Example 35 (a) except that

2-Ethoxyethylamine was used instead of n-propylamine. ¹ H NMR (DMSO-d 6) δ 13.30 (s, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.45 (t, J = 6.2 Hz, 1H), 8.18 (d, J = 8.5 Hz, 1H), 7.93 (m, 2H), 7.80 (dt, J = 1.7, 7.5 Hz, 1H), 7.65 (d J = 7.7 Hz, 1H), 7.60-7.45 (m, 3H), 7.36-7.23 (m, 3H), 7.17 (d, J = 8.3 Hz, 1H), 7.07 (m, 1H), 3.50 (m, 6H), 1.10 (d, J = 7.0 Hz, 3H). Anal. Calcd for CH ₂ N ₄ O ₂ SO 0.5 CH ₂ Cl ₂ : C, 62.89; H, 5.17; N, 11.50; S, 6.58.

Found: C, 62.45, H, 5.33, N, 11.25, S, 6.55.

Example 35 (aa)

6- [2 - ((3-methoxybenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

241

The compound of Example 35 (aa) was prepared in a similar manner to that described in Example 35 (a) except that

3-methoxybenzylamine was used in place of n-propylamine. ¹ H NMR (DMSO-d 6) δ 13.30 (s, 1H), 8.97 (t, J = 5.5 Hz, 1H), 8.60 (d, J = 4.2 Hz, 1H), 8.18 (d, J = 8.7 Hz, 1H); 7.93 (d, J = 16.3 Hz,

1H), 7.80 (dt, J = 1.7, 7.5 Hz, 1H), 7.65 (d, J = 7.9 Hz, 1H),

7.60-7.51 (m, 3H), 7.38-7.15 (m, 5H), 7.08 (m, 1H), 6.94 (m,

2H), 6.80 (dd, J = 8.1, 1.5 Hz, 1H), 4.44 (d, J = 6.6 Hz, 2H),

3.71 (s, 3H). Anal, calcd for C ₂₄ gH ₂ N4O ₂ S · 0.4 H ₂ 0: C, 60.25, H, 4.50, N, 17.57, S, 8.04. Found: C, 60.14, H, 4.47, N,

17.42, S, 8.00.

Example 35 (bb)

6- [2 - ((fur-2-yl) methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin

2-yl) ethenyl] -lH-indazole

The compound of Example 35 (bb) was prepared in a similar manner to that described in Example 35 (a) except that

2-Aminomethylfuran was used in place of n-propylamine. ¹ H NMR (DMSO-d 6) δ 13.31 (s, 1H), 8.93 (t, J = 5.7 Hz, 1H), 8.60 (d, J = 4.3 Hz, 1H), 8.19 (d, J = 8.0 Hz, 1H); 7.93 (d, J = 16.5 Hz,

1H), 7.80 (dt, J = 1.9, 7.4 Hz, 1H), 7.66 (d, J = 7.7 Hz, 1H),

7.59-7.48 (m, 4H), 7.30 (m, 4H), 7.37-7.24 (m, 3H), 7.18 (d, J = 9.2 Hz, 1H) 7.06 (d, J = 8.1 Hz, 1H), 6.40 (m, 1H), 6.31 (m, 1H), 4.44 (d, J = 5.3 Hz, 2H) . Anal, calculation. or

C ₂₆ H ₂₀ N ₄ O ₂ S · (0.1 H ₂ O, 75 CH ₂ Cl ₂ ): C, 62.02, H, 4.22, N,

10.82, S, 6.19. Found: C, 61.58, H, 4.30, N, 10.55, S,

6.12.

242

Example 35 (cc)

6- [2- (2-propynylkarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 35 (cc) was prepared in a similar manner to that described for Example 35 (a) except that propargylamine was used instead of propylamine ^{(76%); H} NMR (300 MHz, CDCl) δ 8.56 (m (1H), 7.96 (d, 1H, J = 8.6 Hz), 7.81 (d, 1H, 16.4 Hz), 7.68 (dt, 1H, J = 1.8, 7) 8 Hz), 7.6 (m, 1H), 7.52-7.45 (m, 3H), 7.3-7.23 (m, 3H), 7.16 (m, 2H), 4 , 10 (m,

2), 2.20 (t, 1H, J = 2.6 Hz). LCMS (100% area) R t = 3.36 minutes (pos) [M + H] / z calcd 411.1, measured 411.1. Analyzed with 0.2 H ₂ O, 0.17 DMF, 1.2 dichloromethane, calculated: C (58.44), H (4.19), N (11.05), S (6.07). Found: C (58.18), H (4:11), N (10.98), S (6.05).

Example 35 (dd)

6- [2- (ethoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of the Example was prepared in a similar manner to that described in Example 35 (a) except that

243 ethoxyamine was used instead of propylamine: ¹ H NMR (300 MHz, CDCl ₃ ) δ 11.60 (s, 1H), 8.71 (d, 1H, J = 7.9 Hz), 8.30 (d, 1H J = 8.5 Hz), 8.05 (d, 1H, J = 16.4 Hz), 7.91 (dt, 1H, J = 1.7,

7.7 Hz), 7.76 (d, 1H, J = 7.8 Hz), 7.67 (m, 2H), 7.56 (dd, 1H,

J = 1.8, 7.3 Hz), 7.52-7.36 (m, 3H), 7.28 (m, 2H), 4.06 (q,

2H, J = 7.0 Hz), 1.31 (t, 2H, J = 7.0 Hz), LCMS (100% area)

R t = 3.28 min (pos) [M + H] / z calcd 417.1, measured

417.1. Analyzed with 0.2 H ₂ O, calculated: C (65.53), H (4.98), N (13.05), S (7.48). Found: C (65.66), H (4.91), N (12.75), S (7.44).

Example 35 (ee)

6- [2- (2-methyl-2-propenylkarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 35 (ee) was prepared in a similar manner to that described in Example 35 (a) except that 2-methylallylamine was used instead of propylamine: ¹ H NMR (300 MHz, CDCl 3) δ 8.56 (m, 1H ), 7.98 (d, 1H, J = 8.5 Hz), 7.81 (d, 1H, J = 16.4 Hz), 7.69 (dt, 1H, J = 1.7, 7, 7 Hz), 7.60 (m,

1H), 7.53-7.42 (m, 3H), 7.32-7.24 (m, 3H), 7.16 (m, 2H), 6.72 (m, 1H), 4.89 (s, 1H), 4.81 (s, 1H), 3.90 (d, 2H, J = 5.5 Hz),

1.71 (s, 3H). LCMS (100% area) R t = 3.37 min (pos) [M + H] / z calcd 427.1, measured 427.1. Analyzed with 0.7 H ₂ O, 0.1 dichloromethane, calculated C (67.35), H (5.31), N

244 (12.52), S (7.16). Found: C (67.55), H (5.39), N (12.35), S (7.15).

Example 35 (ff)

6- [2 - ((3-fluorobenzyl) methylcarbamoyl) phenylsulfanyl] -3-E- [2 (pyridin-2-yl) ethenyl] -1H-indazole

Example 35 (ff) was prepared in a similar manner to that described in Example 35 (a) except that

3-fluorobenzylamine was used instead propylamine: ^X H NMR (300 MHz, CDCl) δ 8.60 (m, IH), 7.97 (d, IH, J = 8.5 Hz), 7.86 (d,

1H, J = 16.4 Hz), 7.70 (m, 2H), 7.51 (m, 2H), 7.33 (m, 4H),

7.18 (m, 2H), 7.11 (dd, 1H, J = 1.6, 8.5 Hz), 6.95 (m, 3H),

4.51 (d, 2H, J = 5.7 Hz), LCMS (100% region) R t = 3.55 min (pos) [M + H] / z calcd 481.1, measured 481.1. Analyzed with 0.7 H ₂ O, 0.5 dichloromethane, calculated: C (63.91), H (4.40), N (10.46), S (5.99). Found: C (63.80), H (4.34), N (10.34), S (5.98).

Example 35 (gg)

6- [2- (2- (methylamino) ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

245

The compound of Example 35 (gg) was prepared in a similar manner to that described for Example 35 (a) except that N-methylethylenediamine was used instead of propylamine: ^X H NMR (300 MHz, CDC1 ₃₎ delta 8.60 (m, 1H), 7.98 (d, IH, J = 8.5 Hz), 7.81 (d, IH, J = 16.4 Hz), 7.69 (dt, IH, J = 1.7, 7) 7 Hz), 7.52 (m, 1H), 7.50-7, 40 (m, 3H), 7.30-7.20 (m, 3H), 7.16 (m, 2H), 3 45 (t, 2H), 2.69 (t, 2H), 2.15 (bs, 3H), LCMS (100% region) Rt =

3.16 minutes (pos) [M + H] / z calcd 430.1, measured 430.1. Analyzed with 0.2 H ₂ O, 0.6 dichloromethane, 0.06 hexane, calculated: C (61.28), H (5.24), N (14.31), S (6.55).

Found: C (61.26), H (5.14), N (14.22), S (6.56).

Example 35 (hh)

6- [2- (2- (Thien-2-yl) ethylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 35 (hh) was prepared in a similar manner to that described for Example 35 (a) except that 2- (2-aminoethyl) thiophene was used instead propylamine: ^X H NMR (300 MHz, CDCI3) 8, 56 (m, 1H), 7.98 (d, 1H, J = 8.5 Hz), 7.81 (d, 1H, J = 16.4 Hz), 7.69 (dt, 1H, J = 1) 7,7,7 Hz), 7,60 (m, 1H), 7,53-7,42 (m, 3H), 7,32-7,24 (m, 3H), 7,16 (m, 3H) 2H), 6.72 (m, 1H), 6.63 (m, 1H), 6.52 (m, 1H), 3.45 (q, 2H), 3.00 (t, 2H). Analyzed with 0.5 H ₂ O, 0.07 dichloromethane, calculated, C (65, 35), H (4.69), N (11.26), S (12.82). Found: C (65.49), H (4.80), N (11.21), S (12.77).

246

Example 35 (ii)

6- (2- (aminocarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 35 (ii) was prepared in a similar manner to that described in Example 35 (a) except that hydrazine was used in place of propylamine: ¹ H NMR (300 MHz, DMSO-d 6) δ 13.3 (s, 1H 9.57 (s, 1H); 8.54 (d, 1H, J = 3.9)

Hz), 8.14 (d, 1H, J = 8.5 Hz), 7.89 (d, 1H, J = 16.4 Hz), 7.73 (dt, 1H, J = 1.7, 7) 6 Hz), 7.60 (d, 1H, J = 7.9 Hz), 7.50 (m,

2H), 7.40 (dd, 1H, J = 1.8, 7.1 Hz), 7.3-7.1 (m, 4H), 7.0 (m, 1H). LCMS (100% area) R t = 0.55 min (pos) [M + H] / z calcd 388.1, measured 388.1. Analyzed with 0.1 DMF, 0.55

EtOAc, 0.12 toluene (NMR) and 0.15 H ₂ O, calculated: C (63.98), H (5.15), N (15.63), S (7.02). Found: C (63.99), H (5.07), N (15.75), S (6.89).

Examples 35 (jj) -35 (nn) can be prepared in a similar manner to that described in Example 35 (a).

N

247

Example 35 (kk)

Example 35 (mm)

Example 35 (nn)

248

Example 36 (a)

6- [2- (N ² - (1-methylimidazol-2-ylmethylidene) hydrazino) carbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

mg (0.103 minol) of the compound prepared in Example 35 (ii) was treated with 29 mg (0.258 mmol, 2.5 eq.) of 1-methyl-2-imidazole carboxaldehyde in ethanol to give Example 36 (a): ^{Σ Η} NMR (300 MHz, DMSO-d 6 δ 8.60 (m, 2H),

8.31 (s, 1H), 8.18 (d, 1H), 8.02 (d, 1H), 7.98 (d, 1H), 7.80 (m, 2H), 7.63 (m 2H, 7.40 (m, 3H), 7.30 (m, 1H), 7.20 (m, 1H), 7.02 (m, 2H), 6.93 (s, 1H), 4 00 (s, 3H), LCMS (100% area) Rt = 4.0 min (pos) [M + H] / z calcd 480.2, measured 480.2. Analyzed with 1.45 H ₂ O, calculated: C (61.76), H (4.76), N (19.39), S (6.34). Found: C (61.78), H (4.67), N (19.34), S (6.39).

Example 36 (b)

6- [2- (N ² - (pyrid-2-ylmethylidene) hydrazino) carbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

249

The compound of Example 36 (b) was prepared in a similar manner to that described in Example 36 (a) except that 2-pyridylcarboxaldehyde was used in place of 1-methyl-2imidazolecarboxaldehyde: ¹ H NMR (300 MHz, CDCl 3) δ 8.57 (m, 2H)

8.45 (m, 2H), 8.22 (d, 1H), 8.10 (s, 1H), 7.93 (d, 1H), 7.83 (d, 1H), 7.8-7 1 (m, 11H), LCMS (100% area) Rt = 4.0 min (pos) [M + H] / z calcd 477.1, measured 477.1, Analyzed with 0.85 H ₂ O, calculated: C (65, 93), H (4.45), N (17.09), S (6.52). 95), S (6.38).

Example 36 (c)

6- [2- (N ² - (2,2,2-Trifluoroethylidene) hydrazino) carbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl) -1H-indazole

Example 36 (c) was prepared in a similar manner to that described in Example 36 (a) except that trifluoroacetaldehyde was used instead of 1-methyl-2-imidazolecarboxaldehyde: ² H NMR (300 MHz, DMSO-d 6) δ 8 70 (m, 1H); 8.25 (m, 1H); 8.02 (d, 1H); 7.90 (dt, 1H); 7.80-7.20 (m, 10H). LCMS (100% area) R t = 5.64 min (pos) [M + H] / z calcd 468.1, measured 468.0. Analyzed with 0.75 H ₂ O Calc'd, C (57.39), m.p.

250

H (3.67), N (14.56), S (6.67). Found: C (57.44), H (3.67),

N (14.56), S (6.67).

Example 37 (a)

6- [6-Fluoro-2- (ethoxycarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 37 (a) was prepared in a similar manner to that described in Example 35 (a) except that the starting material described below was used and that ethoxyamine was used instead of propylamine: ¹ H NMR (300 MHz, CDCl 3) δ

8.59 (M, 1H), 8, 08 (D, 1H), 7.88 (D, 1 H, J = 16.4 Hz), 7.79 (T, 1H), 7, 65 (D, 1H), 7, 60 (M, 1H), 7.50 (d, 1H, J = 16.4 Hz), 7, 40 (T, 1H), 7,36 (D, 1H), 7.28 (s, 1 H), 7.23 (m, IH); 7.10 (D, 1H), 3, 90 (Q, 2H), 1.19 (T, 3H). LCMS (100% area)

R t = 4.85 min (pos) [M + H] / z calcd 435.1, measured

435.1, (neg) [MH] / z calcd. 433.1, measured 433.1. Analyzed with 0.35 H ₂ O, 0.07 EtOAc calculated: C (62, 56), H (4.57), N (12.54), S (7.17). Found: C (62.61), H (4.55), N (12.49), S (7.11).

The starting material was prepared as follows:

(I)

251

A solution of 1.07 g (5.75 mmol) of ethyl 2,3-difluorobenzoate in 10 mL of DMF was treated with 896 mg (11.5 mmol, 2.0 eq) of sodium sulfide at 23 ° C. The mixture was stirred under argon for 10 hours. The solution was diluted with 50 mL of ethyl acetate and 50 mL of water and 5 mL of 10% citric acid. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over sodium sulfate, decanted, and concentrated under reduced pressure to give 3-fluoro-2-mercaptobenzoic acid ethyl ester: ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.71 (t, 1H ), 7.38 (m, H), 7.12 (m, 1H), 4.41 (q, 2H), 1.40 (t, 3H), LCMS (100% area) Rt = 4.53 min (pos) [M + H] / z calcd 201.0, measured 200.9.

(Ii)

320 mg (39%) of the above thioether was prepared in a similar manner to that described in Example 33 (a), step (iii) except that 3-fluoro-2-mercaptobenzoic acid ethyl ester was used in place of thiosalicylate: FTIR (thin 2952, 1727, 1607, 1586, 1564, 1469, 1433, 1366, 1292, 1249,

182, 1141, 1074, 836 cm ^-1; H NMR (300 MHz, CDCl3) δ 8.62 (m,

1H), 7.90 (d, 1H, J = 8.6 Hz), 7.85 (d, 1H, J = 16.4 Hz), 7.67 (dt, 1H, J = 1.8, 7) 7 Hz), 7.57-7.38 (m, 5H), 7.23-7.10 (m,

3H), 5.65 (s, 2H), 4.34 (q, 2H, J = 7.1 Hz), 3.56 (t, 2H, J =

8.2 Hz), 1.30 (t, 3H, J = 7.1 Hz), 0.88 (t, 2H, J = 8.2 Hz), -

0.06 (s, 9H), LCMS (100% area) R t = 4.44 min (pos) [M + H] / z calc. 549.2, measured 549.2.

252 (iii)

303 mg (99%) of the carboxylic acid listed above was prepared in a similar manner to that described in Example 33 (a), step (iv): FTIR (thin film) 2953, 2496, 1715, 1663,

1607, 1567, 1470, 1434, 1300, 1250, 1221, 1075, 967, 932.836 cm ^{-1, 3} H NMR (300 MHz, CDC1 ₃₎ delta 8.81 (m, 1H), 7.87 (m, 2H ), 7.79 (m, 3H), 7.65 (m, 2H), 7.56 (m, 1H), 4.40 (m, 1H), 7.30 (m,

1H), 7.00 (dd, 1H, J = 1.4, 8.5 Hz), 5.58 (s, 2H), 3.59 (t,

2H, J = 8.2Hz), 0.93 (t, 2H, J = 8.2Hz), -0.01 (s, 9H), LCMS (100% area) Rt = 10.47 minutes (pos ) [M + H] / z calcd

522.2, measured 522.2.

(Iv)

The above salt was prepared in a similar manner to that described for Example 33 (g): ^X H NMR (300 MHz, DMSO-de) δ

13.2 (s, 1H), 8.68 (M, 1H), 8.12 (d, 1 H, J = 8.5 Hz), 7. 98 (D, 1 H, J = 16.4 Hz), 7 , 88 (Dt, 1H, J = 1.8, 7.6 Hz), 7.73 (d, 1H, J = 7.9 Hz), 7.61 (D, 1H, J = 16.4 Hz: 7,73-7,32 (m, 3H),

7.20 (m, 2H), 7.07 (t, 1H), 3.23 (m, 8H), 1.68 (m, 8H),

1.41 (m, 8H); 1.04 (t, 12H).

(in)

253

The above pentafluorophenyl ester was prepared in a similar manner to that described in Example 35 (a), step (i): LCMS (100% area) R t = 10.53 min (pos) [M + H] / z calcd 558.1, measured 558.1.

Example 37 (b)

6- [6-Fluoro-2- (cyclopropylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 37 (b) was prepared in a similar manner to that described in Example 37 (a) except that cyclopropylamine was used instead of ethoxyamine: ¹ H NMR (300 MHz, DMSO-d 6) δ 8.42 (m, 1H 8.28 (d, 1H), 7.83 (d, 1H), 7.75 (m, 2H), 7.60 (m, 1H), 7.31 (m, 2H), 7.15 (m, 4H), 6.86 (d, 1H), 2.58 (m, 1H), 0.42 (m, 2H), 0.23 (m, 2H). LCMS (100% area) R t = 4.91 min (pos) [M + H] / z calcd 431.1, measured 431.1, (neg). [MH] / z calcd 429.1, measured

429.2. Analyzed with 0.55 _H2O Calc'd, C (65.46), H (4.60),

N (12.72), S (7.28). Found: C (65.52), H (4.58), N (12.64),

S (7.06).

Example 37 (c)

6- [6-fluoro-2- (isopropoxycarbamoyl) phenylsulfanyl] -3-E- [2 (pyridin-2-yl) ethenyl] -1H-indazole

254

The compound of Example 37 (c) was prepared in a similar manner to that described in Example 37 (a) except that isopropoxyamine was used instead of ethoxyamine: ¹ H NMR (300C)?

MHz

CDC1 ₃ ) δ 9.50

1H),

7.72 (d,

1H), 7.68 (d,

1H, J = 16.4

Hz), 7.54 (dt, 1 H),

7.35 (m, 4H).

7.20 (m,

4H),

4.03 (m,

1H),

1.07 (d, 6H), LCMS (100% area)

R t = 4.90 min (pos) [M + H] / z calcd 449.1, measured 449.1.

Analyzed p

0.1 DMF, (4.87), N (12.45), S (6.95). Found: C (63.22), H (4.84), N (12.37), S (6.91).

Example 37 (d)

6- [6-fluoro-2- (methylcarbamoyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 37 (d) was prepared in a similar manner to that described in Example 37 (a) except that methylamine was used in place of ethoxyamine: ¹ H NMR (300 MHz, DMSO-d 6) δ 8.37 (m, 1H 8.18 (m, 1H); 7.87 (d, 1H); 7.67 (d, 1H);

1H, J = 16.4Hz), 7.59 (dt, 1H), 7.40 (d, 1H), 7.30 (m, 2H),

7.20 (m, 4H), 6.85 (d, 1H), 2.49 (d, 3H), LCMS (100% area)

R t = 4.63 minutes (pos) [M + H] / z calcd 405.1, measured

405.2, (neg) [M-H] / z calcd. 403.1, measured 403.1.

255

Analyzed with 0.2 DMF, 0.3 CH 2 Cl 2 (nmr), 0.3 H ₂ O, calculated: C (61.13), H (4.39), N (13.07), S (7.13) ). Found: C (61.08), H (4.35), N (13.14), S (7.22).

Example 38 (a)

6- [2- (2-methyl-quinolin-6-ylcarbamoyl) phenylsulfanyl] -3-E- (2styryl) -lH-indazole

The compound of Example 38 (a) was prepared in a similar manner to that described in Example 33 (b) except that steps (i) and (ii) were omitted: ¹ H NMR (300 MHz, CDCl 3) δ 8.58 ( s, 1H), 8.13 (s, 1H), 7.80 (m, 3H), 7.67 (t, 1H), 7.43 (m,

2H), 7.34-7.16 (m, 9H), 7.13 (d, 1H), 7.07 (d, 1H), 2.60 (s,

3H). LCMS (100% area) R t = 3.87 min (pos) [M + H] / z calcd 513.1, measured 513.2.

Example 38 (b)

6- [2 - ((4-piperazin-1-yl-3-trifluoromethylphenyl) carbamoyl) phenylsulfanyl] -3-E- (2-styryl) -1H-indazole

NH

The compound of Example (b) was prepared as described in Example 38 (a) except

3-Trifluoromethyl-4-piperazin-1-yl-phenylamine was similar to that used

256

instead of 6-amino-2-methylquinoline: ^X H NMR (300 MHz CDCI3) δ 8.75 (s, 1 H), 7.95 (d, 1 H), 7.77 (M, 2H), 7, 69 (with, 1H), 7.55 (m, 3H) 7.40-7.25 (m, 9H). 7.20 (D, 1H), 3.00. (M, 4H), 2.83 (m, 4 H). LCMS (100% area) Rt = ^: 3, 94 minutes (pos ) [M + H] / z

calculated 600.2, measured 600.2. Analyzed with 0.1 hexane (nmr), 1.4 H ₂ O, calculated: C (63.71), H (5.12), N (11.06), S (5.06). Found: C (63.67), H (5.06), N (10.98), S (5.00).

Example 39 (a)

6- [2- (methylcarbamoyl) phenylamino] -3-E- [2- (pyridin-2-yl) ethenyl] indazole-H

A solution of 39 mg (0.077820 mmol) of N-methyl-2- [3 - ((E) -2-pyridin-2-ylvinyl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazol-6-ylamino] -benzamide (synthesis described below), 21 μΐ (0.3128 mmol) of ethylenediamine and 0.63 ml (0.6256 mmol) of IM TBAF in THF were stirred in an oil bath at 90 ° C for 2 hours. The crude reaction mixture was diluted with 50 mL of ethyl acetate, extracted with 2 x 20 mL of 1M sodium bicarbonate solution, 5 x 20 mL of brine, dried over magnesium sulfate, filtered and concentrated to a solid. The solid was dissolved in THF, concentrated to an oil, then triturated with a mixture of CH 2 Cl 2 and Et ₂ O, causing a powder to precipitate. The powder was collected by filtration, washed with Et ₂ O and dried under high vacuum. The weight of the solid collected was 20 mg (70% yield). ¹ H NMR (DMSO-d 6) δ 12.91 (bs, 1H), 9.86 (s, 1H), 8.60 (d, J = 4.0 Hz, 1H), 8.52 (m, 1H),

257

8.08 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 16.4 Hz, 1H), 7.80 (dt, J = 1.7, 7.5 Hz, 1H 7.65 (d, J = 7.9 Hz, 1 H), 7.51 (d, J =

16.1 Hz, 1H), 7.47-7.34 (m, 2H), 7.25 (m, 2H), 7.00 (d, J =

9.6 Hz, 1H), 6.89 (t, J = 7.0 Hz, 1H), 2.79 (d, J = 4.7 Hz,

3H). 7 \ nal. Calcd for C 22 H 19 N 5 O · 0.5 CH ₂ Cl ₂ : C, 65.61, H, 4.89, N, 17.00. Found: C, 65.52, H, 5.08, N, 16.78.

The starting material was prepared as follows:

258 i

A solution of 191 mg (0.4 mmol) of 6-iodo-3-carboxaldehyde-1- [2- (trimethylsilanyl) ethoxymethyl] -1H-indazole (from Example 33 (a), step (ii)), 120.1 mg (0 , 8 mmol) of methyl anthranilate, 28 mg (0.08 mmol) of 2- (dicyclohexylphosphino) biphenyl, 18.4 mg (0.02 mmol) of Pd ₂ (dba) ₃ , 212.3 mg (1.0 mmol) of K ₃ PO ₄ , dissolved in 1.0 mL dry DME, was purged with argon 3 times under vacuum, then stirred under argon for 3 days in an oil bath at 80 ° C. The crude mixture was filtered through a short column of SiO ₂ eluting with ethyl acetate and then purified by ring-plate chromatography with 25% CH ₃ CN and CH ₂ Cl ₂ . The weight of the pure fractions was 42 mg. An additional 120 mg of product was also collected, which was ~ 90% pure. The overall yield of N-methyl-2- [3 - ((E) -2-pyridin-2-ylvinyl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazol-6-ylamino] benzamide was 162 mg or ~ 81%.

Example 39 (b)

6- [2- (prop-2-ynylcarbamoyl) phenylamino] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

The compound of Example 39 (b) was prepared in a similar manner to that described in Example 39 (a) except that

259 Propargylamine was used instead of methylamine. ^{@ 1} H NMR (CDCl3) .delta

9.50 (s, 1H), 8.64 (d, J = 4.5Hz, 1H), 7.98 (d, J = 8.9Hz,

1H), 7.90 (d, J = 16.4 Hz, 1H), 7.70 (dt, J = 1.7, 7.5 Hz,

1H), 7.57 (d, J = 16.3 Hz, 1H), 7.52-7.43 (m, 3H), 7.34 (dt, J = 1.5, 7.2 Hz, 1H) 7.26 (m, 3H), 7.34 (ddd, J = 1.0, 4.9, 7.5)

Hz, 1H), 7.09 (dd, J = 1.7, 9.0 Hz, 1H), 6.85 (dt, J = 1.0,

7.0 Hz, 1H), 6.33 (bs, 1H), 4.24 (dd, J = 2.6, 5.3 Hz, 2H), 2.30 (t, J = 5.5 Hz) , 1H). Anal, calcd for C 24 H 19 N 5 O · 0.25 CH 2 Cl 2: c, 70.24, H, 4.74, N, 16.89. Found: C, 70.72, H, 4.96, N, 16.55.

Example 40 (a)

6- (3-aminobenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl-lH-indazole

NH ₂

Example 40 (a) was prepared in a similar manner to that described in Example 11. ¹ H NMR (300 MHz, DMSO-d 6) δ 13.5 (s, 1H), 8.62 (d, 1H, J = 3.86 Hz), 8.34 (d,

1H, J = 8.5 Hz), 8.01 (d,

7.83 (td, 1H, J = 7.69Hz,

7.29 (qd, 1H, J = 7.39Hz,

7.77), 7.00 (t, 1H, J = 1.86 = 1.40 Hz), 6.86 (m, 1H);

1H, J = 16.36 Hz), 7, 87 (with, 1H), J = 1.81 Hz), 7.58-7.71 (M, 3H), J = 0.98 Hz); 7, 21 (T, 1H, . J = Hz), 6.90 (Dt, 1 H, J = 6, 15 Hz, J >, 40 (w, 2H). MS (ESI +) [M + H] / z

calculated 446, measured 446. Calculated: C, 74.10, H, 4.74,

N, 16.46. Found: C, 72.72; H, 4.87; N, 16.02.

The starting material was prepared as follows:

260 i

BÍOHfe

To 8.22 g (60 mmol) of m-aminophenylboronic acid in 60 ml of dimethylformamide at 23 ° C under argon was added 10 ml (72 mmol) of triethylamine and 0.366 g (3 mmol) of 4- (dimethylamino) pyridine. The resulting solution was heated to 50 ° C. 20.4 g (72 mmol) of carbonic acid 4-nitrophenyl ester 2-trimethylsilanylethyl ester was added in 5 portions of 4 g for 18 hours. After 44 hours, 3.4 g (12 mmol) was added.

Carbonic acid 4-nitrophenyl ester-2-trimethylsilanylethyl ester followed by 1.7 ml (12 mmol) of triethylamine. After 63 hours, the reaction mixture was concentrated to an oil. Purification by chromatography on silica, eluting with ethyl acetate: hexane 3: 7 to 7: 3 afforded 8.12 g (48%) 2-trimethylsilanyl (3-borónfenyl) -carbamic acid: R _f sm 0.067, p 0.33 (ethyl hexane 1: 1), ¹ H NMR (300 MHz, CD ₃ OD) δ 7.64 (s, 1H), 7.49 (d, 1H, J = 8.94 Hz), 7.26 (m, 2H )

4.23 (t, 2H, J = 8.28 Hz), 1.06 (t, 2H, J = 8.21 Hz) 0.72 (s, 9H). MS (ESI) [M + Na] / z calcd 304, found 304.

(Ii)

A mixture of 7.1 g (14.8 mmol) of 6-iodo-3 - ((E) -2-pyridin-2-ylvinyl) -

1- (2-trimethylsilanylethoxymethyl) -1H-indazole, 8.32 g (29.6 mmol) of (3-boronic acid-phenyl) -carbamic acid 2-trimethylsilanylethyl ester, 312 mg (0.44 mmol) of dichlorobis-

261 (triphenylphosphine) palladium (II), 6.13 g (44.4 mmol) potassium carbonate and 2.1 ml (14.8) triethylamine in 60 ml anisole were heated to 80 ° C under a carbon monoxide atmosphere. After 24 hours, an additional 2.1 mL (14.8 mmol) of triethylamine was added. After 33 hours, TLC analysis indicated that the reaction was complete (7: 3 ethyl acetate / hexane). The reaction mixture was cooled to 23 ° C, and then diluted with 40 mL of saturated aqueous NaHCO 3 and 300 mL of ethyl acetate. The phases were separated and the aqueous phase was extracted with 2 x 100 mL ethyl acetate. The combined ethyl acetate layers were washed with 100 mL brine, and dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel chromatography afforded 7.22 g (79%) of (3- {1- [3- (2-pyridin-2-ylethyl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazol-6-yl] methanoyl} phenyl 2-trimethylsilanylethyl ester ) of carbamic acid as a yellow glass. ³ H NMR (300 MHz,

CDC13 ) δ 8.65 (d, 1 H) , J = 3, 93 Hz), 8.10 (d, 1 H, J = 8.54 Hz), 8, 04 (with, 1H), 7.94 (D, 1H, J = 16.33 Hz), 7.82 ( S, 1H) , 66- 7.77 (M, 3H), 7, 61 (D, 1H, J = 16.35 Hz), 7.40- 7.51 (m, 3H), 7.19 (M, 1H), 7.00 (with, 1H) 5.77 (s, 2H), 4.25 (t, 2H) J = 6, 93 Hz) , 3.6 0 (t, 2H, J = = 8.10 Hz), 1.04 (t, 2H, J = 6.79 Hz), 1.0 0 (t, 2H, J = 8 / 13 Hz), 0.04 (s, 9H), O, 0 (s, 8H) . MS

(ESI +) [M + H] / z calcd 615, measured 615.

Example 40 (b)

6- (3-Amino-4-methylbenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1Hindazole

N H

62

Example 40 (b) was prepared in a similar manner to Example 40 (a) except that in step (i) 4-methyl-3-aminophenylboronic acid prepared as described below was used in place of m-aminophenylboronic acid . ^X H NMR _(DMSO-d6) δ 13, 6 (s, 1H), 8, 62 (d, 1 H, J =

3.81 Hz), 8.33 (d, 1H, J = 8.47 Hz), 8.01 (d, 1H, J = 16.36)

Hz), 7.85 (s, 1H), 7.82 (dd, 1H, J = 7.60 Hz, J = 1.80 Hz),

7.70 (d, 1H, J = 7.81 Hz), 7.63 (d, 1H, J = 16.36 Hz), 7.57 (dd, 1H, J = 8.47 Hz, J = 1) 2 Hz), 7.29 (m, 1H), 7.12 (d, 1H, J = 7.82 Hz), 7.09 (d, 1H, J = 1.64 Hz), 6.90 ( dd, 1 H, J =

7.59 Hz, J = 1.65 Hz), 5.16 (bs, 1H), 2.16 (s, 1H). MS (ESI +) [M + H] / z calcd 355, Anal calcd: C, 74.56, H, 5.12, N, 15.81. Found: C, 73.86, H, 5.25, N, 15.34.

The starting material was prepared as follows:

A mixture of 3.34 g (18.45 mmol) of 4-methyl-3-nitrophenylboronic acid and 334 mg of 10% Pd / C in 30 mL of MeOH was hydrogenated at 1 atm at 23 ° C. After 22 hours, the reaction mixture was filtered through celite and concentrated to give 2.53 g (91%).

3-amino-4-methylphenylboronic acid. ¹ H NMR (300 MHz, DMSO-d 6) δ 7.21 (s, 1H), 7.08 (d, 1H, J = 7.5 Hz), 6.92 (d, 1H, J = 7.46) Hz), 4.81 (bs, 2H), 2.09 (s, 3H). MS (ESI) [M + H] / z calcd 152, found 152.

Example 40 (c)

6- (5-Amino-2,4-dimethylbenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] 1H-indazole

263

The compound of Example 40 (c) was prepared in a similar manner to Example 40 (a) except that in step (i) 2,4-dimethyl-3-aminophenylboronic acid (prepared as described below) was used in place of m-aminophenylboronic acid: ¹ H NMR (DMSO-d 6) δ 8.62 (d, 1H, J = 3.78 Hz), 8.32 (d, 1H, J = 8.48 Hz), 7.99 (d, 1H, J = 16.35 Hz), 7.83 (td, 1H, J = 7.68 Hz, J = 1.8 Hz), 7.80 (s, 1H), 7.69 (d, 1H, J = 7 80 Hz), 7.64 (dd, 1H, J = 8.47 Hz, J = 1.27 Hz), 7.62 (d, 1H, J = 16.36 Hz), 7.29 (m, 1H), 6.94 (s, 1H), 6.64 (s, 1H), 4.87 (bs, 2H), 2.12 (s, 3H), 2.10 (s, 3H). LCMS (ESI +) [M + H] / z calcd 369, measured 369. Anal, calcd: C, 74.98, H, 5.47, N, 15.21. Found: C, 73.85, H, 5.56, N, 14.49.

The starting material was prepared as follows:

(I)

2,4-Dimethylphenylboronic acid was formed in a similar manner to Example 24 (a), step (vii) except that 2,4-dimethylbromobenzene was used as the starting material. ¹ H NMR (CD ₃ OD) δ 7.13 (d, 1H, J = 7.43 Hz), 7.00 (s, 1H), 6.97 (d, 1H, J = 7.49 Hz), 2.28 (s, 3H); 2.28 (s, 3H). LCMS (ESI +) [M + H] / z calcd 151, found 151.

264 ·

BíOHk

To 1 mL of -40 ° C cooled nitric acid was added 1 mL of TFA. The resulting mixture was allowed to warm somewhat to -35 ° C and 150 mg (1 mmol) was added in one portion.

2,4-dimethylphenylboronic acid. After 1 hour ice was added and the heterogeneous mixture was filtered. The resulting solid was suspended in Et ₂ O and extracted with 1 mL 3N aqueous NaOH, then 2 mL water. The aqueous phase was acidified with 1 mL of 3N aqueous HCl and extracted again with 3 x 5 mL of EtOAc. The combined organic layers were washed with brine, dried over Na ₂ SO _{4 /} decanted and concentrated to give 93 mg (47%) of 2,4-dimethyl-5-nitrophenylboronic acid. LCMS (ESI +) [M + H] / z calcd 196, found 196.

(Iii)

3-Amino-4,6-dimethylphenylboronic acid was prepared in a similar manner to that described in Example 40 (b), step (i). ¹ H NMR (CD ₃ OD) δ 6.83 (s, 2H), 6.64 (s, 1H), 2.17 (s, 3H),

2.13 (s, 3H).

Example 41 (a)

6- [3 - ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) benzoyl] -3E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

265

To a solution of 323 mg (2.1 mmol, 2.1 eq.) Of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid in 5 mL of DMF at 23 ° C under argon was added 365 μΐ (2.1 mmol, 2.1 eq) diisopropylethylamine, 798 mg (2.1 mmol, 2.1 eq) HATU and catalytic amount of DMAP. To the resulting solution was added 340 mg (1 mmol, 1 eq.) Of 6- (3-aminobenzoyl) -3-E- (2-pyridin-2-yl) ethenyl) -ΙΗ-indazole (Example 40 (a)). The reaction was then monitored by HPLC until all of the starting analine was consumed for ~ 2 hours (giving a mixture of mono and bis acylated compounds). The reaction mixture was quenched with saturated NaHCO ₃ , then diluted with water and extracted with ethyl acetate. The combined EtOAc layers were washed with water, brine, dried over Na ₂ SO ₄ , filtered and concentrated to an oil. The oil was dissolved in 10 mL of methanol, 290 mg (2.1 mmol, 2.1 eq.) Of K ₂ CO _{3 was added,} and the resulting mixture was stirred at 23 ° C until the bis-acylated compound was consumed (~ 30 min). . The reaction mixture was concentrated to an oil, then partitioned between water and EtOAc. The organic phases were washed with brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel chromatography (1: 1-8: 2 ethyl acetate-dichloromethane) gave the compound of Example 41 (a). ¹ H NMR (300 MHz, DMSO-d ₆ ) δ 13.6 (s, 1H), 10.3 (s, 1H), 8.62 (d, 1H, J = 3.88 Hz), 8.38 (d, 1H, J = 8.51Hz), 8.20 (s, 1H), 8.12 (td, 1H, J = 7.58Hz, J =

1.78 Hz), 8.02 (d, 1H, J = 16.36 Hz), 7.93 (s, 1H), 7.83 (td,

1H, J = 7.61Hz, J = 1.7Hz), 7.70 (d, 1H, J = 7.78Hz), 7.65 (d, 1H, J = 16.23Hz), 7 65-7.53 (m, 3H), 7.30 (m, 1H), 4.43 (q, 2H, J = 7.07 Hz), 2.21 (s, 3H), 1.31 ( t, 3H, J = 7.07 Hz).

MS (ESI +) [M + H] / z calcd 477, measured 477. Anal, Calcd:

266

C, 70.57, H, 5.08, N, 7.64. Found: C, 70.46, H, 5.11, N,

17.61.

Example 41 (b)

6- [3- (pyridin-4-ylcarboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 41 (b) was prepared in a similar manner to that described in Example 41 (a) except that isonicotinic acid was used instead of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. NMR (300

8.74 (d, 2H, J = 6.04 Hz); 8.56 (d, 1H, J = 4.14)

2H);

8.05 (dt, 1 H, J)

7.97 Hz, J = 1.64

7.95 (d, 1 H,

J = 16.55

3H),

MHz CD ₃ 0D) δ Hz), 8.27 (m, 8, 02 (s, 1 H), 7.73 (m, 2H)

7, 56-7, 67 m

3H),

7.32 (m, IH). MS (ESI +) [M + H] / z calcd

446, measured

446th

Anal.

Calculation: C, 72.80,

H, 4.30; N, 15.72.

Found: C, 71.59,

H, 4.43; N, 15.33.

Example 41 (c)

6- (3-crotonylamidobenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1H-

The compound of Example 41 (c) was prepared in a similar manner to that described in Example 41 (a) except that

267 crotonic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (300 MHz, DMSO-d 6) δ

13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, J = 3.81 Hz), 8.37 (d, 1H, J = 8.49 Hz), 8.12 (s, 1H); 8.02 (d, 1H, J = 16.34)

Hz), 7.99 (d, 1H, J = 7.88 Hz), 7.83 (td, 1H, J = 7.67 Hz, J =

1.78 Hz), 7.70 (d, 1H, J = 7.85 Hz), 7.65 (d, 1H, J = 16.40)

Hz), 7.63 (dd, 1H, J = 8.43 Hz, J = 1.23 Hz), 7.47-7.56 (m,

2H), 7.29 (qd, 1H, J = 7.39Hz, J = 0.99Hz), 6.82 (m, 1H, J =

6.9 Hz), 6.11 (dd, J = 15.21 Hz, J = 1.68 Hz), 1.87 (d, 3H, J = 6.89 Hz). MS (ESI +) [M + H] / z calcd 409, found 409. 7 µl. Calc'd: C, 73.51; H, 4.94; N, 13.72. Found: C, 72.15; H, 4.97; N, 13.39.

Example 41 (d)

6- [3- (indol-4-ylcarboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 41 (d) was prepared in a similar manner to that described in Example 41 (a) except that 1H-indole-4-carboxylic acid was used in place of 2-ethyl-

5-methyl-2H-pyrazole-3-carboxylic acid. LCMS (ESI +) [M + H] / z calcd 484, found 484.

Example 41 (e)

6- [3 - ((5-acetyltien-2-yl) carboxamido) benzoyl] -3-E- [2- (pyridin

2-yl) ethenyl] -lH-indazole

268

The compound of Example 41 (e) was prepared in a similar manner to that described in Example 41 (a) except that

5-Acetylthiophene-2-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (300 MHz, DMSO-d 6) δ 13.6 (s, 1H), 10.6 (s, 1H), 8.63 (d, 1H, J =

3, 83 Hz), 8.39 (d, 1H, J = 8.51 Hz), 8 20 (with, 1H), 8.14 (Dt, 1H, J = 7, 25 Hz, J = 2.05 Hz), 8, 07 (d, 1H, J = 4, 09 Hz), 8.02 (D, 1H, J = 16.42 Hz), 8.00 (d, 1H, J = 4.01 Hz), 7, 94 (with, 1H), 7, 83 (td, 1 H, J = 7.69 Hz, J = 1, 78 Hz), 7.59 7, 65 (M, 5H), 7.30 (qd, 1 H, J = 7.40 Hz, J = 0.96 Hz ), 2, 58 (p , 3H) . MS

(ESI +) [M + H] / z calcd. 493, measured 493. Anal, Calcd: C,

68.28, H, 4.09, N, 11.37, S, 6.51. Found: C, 66.07, H, 4.34, N, 10.91, S, 6.14.

Example 41 (f)

6- [3- (3,5-Difluorophenylacetamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

The compound of Example 41 (f) was prepared in a similar manner to that described in Example 41 (a) except that (3,5-difluorophenyl) acetic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. acid. ^X H NMR (300 MHz, DMSO-de) δ 13.6 (br s, 1H), 10.5 (s, 1H), 8.62 (d, 1 H, J =

269

4.02 Hz), 8.36 (d, 1H, J = 8.51 Hz), 8.05 (s, 1H), 8.01 (d, 1H, J = 16.38 Hz), 7.93 (d, 1H, J = 7.88Hz), 7.90 (s, 1H),

7.83 (td, 1H, J = 7.61 Hz, J = 1.77 Hz), 7.70 (d, IH, J = 7.85 Hz), 7.64 (d, IH, J = 16 Hz) 33 Hz), 7.61 (dd, 1H, J = 8.45 Hz, J = 1.15 Hz), 7.48-7.57 (m, 2H), 7.15-7.31 (m 5H), 3.77 (s, 2H). MS (ESI +) [M + H] / z calc 495, found 495.

Example 41 (g)

6- [3 - ((5-methyl-1H-pyrazol-3-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

Example 41 (g) was prepared in a similar manner to that described in Example 41 (a) except that

5-Methyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ^X H

NMR (300 MHz, _DMSO-d6) δ 13.6 (br s, IH), 13.0 (br s, IH), 10.3 (br s, IH), 8.63 (d, IH, J = 3.95 Hz), 8.37 (d, 1H, J = 8.66 Hz), 8.36 (s, 1H), 8.16 (d, 1H, J = 7.55 Hz), 8, O 2 (d, 1H, J =

16.37 Hz), 7.93 (s, 1H), 7.83 (dt, 1H, J = 7.61 Hz, J = 1.73

Hz), 7.70 (d, 1H, J = 7.82 Hz), 7, 65 (D, IH, J = 16.36 Hz) 7, 65 (Dd, IH, J = 8 55 Hz, J = 1.12 Hz), 7.52 (m, 2H); 7.29 (M, IH), 6.50 (s, IH), 2 , 29 (with, 3H). MS (ESI &lt; + &gt;) [M + H] / z

calculated 449, measured 449. Anal, Calc .: C, 69.63, H,

4.49, N, 18.74. Found: C, 68.53; H, 4.95; N, 17.47.

270

Example 41 (h)

6- [3 - ((2-RS-trans-methylcyclopropyl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

Example 41 (h) was prepared in a similar manner to that described in Example 41 (a) except that 2-methyl-cyclopropanecarboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid . R _f sm 0.32, R _f p 0.42 (ethyl acetate-dichloromethane 8: 2), ¹ H NMR (300

MHz, DMSO-d 6) δ 13.6 (s, 1H), 10.4 (s, 1H), 8.62 (dd, 1H, J =

4.75 Hz, J = 0.96 Hz), 8.36 (d, 1H, J = 8.47 Hz), 8.06 (t, 1H,

J = 1.67 Hz), 8.01 (D, 1 H, J = 16.37 Hz), 7.90 (m, 2H), 7, 83 (Td, 1H, J = 7.68Hz, J = 1.79 Hz), 7.70 (d, 1H, J = 7.84) Hz); 7.64 (d, 1H, J = 16.35) 7.61 (dd, 1H, J = 8.47 Hz), J = 1.32 Hz), 7.51 (t, 1H, J = 7.69 Hz), 7.45 (dt, 1H, J = 7, 68 Hz, J = 1.50 Hz), 7.29 (dq, 1H, J = 7.41Hz, J = 1.04 Hz), 1.51 (m, 1H), 1.23 (M, 1H), 1.09 (d, 3H, J = 5.93), 1.01 (M, 1H), 0.65 (m, IH). MS 1 (ESI +) [M + H] / z calcd 423, measured 423rd Anal, calculation: c. H, 5.25; N, 13.26. measured : C,

H, 5.56; N, 13.27.

Example 41 (i)

6- [3 - ((1,5-dimethyl-1H-pyrazol-3-yl) carboxamido) benzoyl] -3-E [2- (pyridin-2-yl) ethenyl] -1H-indazole

271

The compound of Example 41 (i) was prepared in a similar manner to that described in Example 41 (a) except that

1,5-Dimethyl-1H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (300 MHz, DMSO-d 6) δ 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d,

1 H, J = 3.87 Hz), 8.37 (d, 1 H, 3 = 8.49 Hz), 8.34 (d, 1 H, J =

1.63 Hz), 8.16 (td, 1H, J = 7.43 Hz, J = 1.96 Hz), 8.02 (d,

1H, J = 16.35 Hz), 7.92 (s, 1H), 7.83 (dt, 1H, J = 7.68 Hz, J = 1.79 Hz), 7.70 (d, 1H, J = 7.84 Hz), 7.65 (d, 1H, J = 16.35 Hz), 7.65 (dd, 1H, J = 8.52 Hz, J = 1.2 Hz), 7.52 (m, 2H)

7.29 (m, 1H), 6.55 (s, 1H), 3.83 (s, 3H), 2.30 (s, 3H). MS (ESI +) [M + H] / z calcd 463, found 463. Anal. Calcd: C, 70.12, H, 4.79, N, 18.17. Found: C, 69.59, H, 4.88, N, 17:86.

Example 41 (j)

6- [3 - ((3-methylpyridin-4-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 41 (j) was prepared in a similar manner to that described in Example 41 (a) except that

3-Methylisonicotinic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (300 MHz, DMSO-d 6) δ 13.6 (s, 1H), 10.7 (s, 1H), 8.62 (dd, 1H, J = 4.72)

Hz, J = 0.86 Hz), 8.57 (s, 1H), 8.55 (d, 1H, J = 4.91 Hz),

8.37 (d, 1H, J = 8.46 Hz), 8.20 (s, 1H), 8.07 (dt, 1H, J = 7.27 Hz, J = 1.99 Hz), O 2 (d, 1H, J = 16.37 Hz), 7.93 (s,

1H), 7.83 (td, 1H, J = 7.69Hz, J = 1.79Hz), 7.70 (d, 1H, J =

7.84 Hz), 7.64 (d, 1H, J = 16.27 Hz), 7.55-7.65 (m, 3H), 7.48

272 (d, 1H, J = 4.89 Hz), 7.30 (qd, 1H, J = 7.39 Hz, 3 = 1.02 Hz),

2.38 (s, 3H). MS (ESI +) [M + H] / z calc 460, found 460.

Example 41 (k)

6- [3- (cyclopropylcarboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 41 (k) was prepared in a similar manner to that described in Example 41 (a) except that the cyclopropanecarboxylic acid was used in place of 2-ethyl-

5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (CDCl 3 / MeOD) δ 8.52 (d, 1H, J = 3.9 Hz), 8.09 (d, 1H, J = 8.5 Hz), 7.93 (s, 1H), 7.85-7.80 (m, 3H), 7.71-7.63 (m, 2H), 7.55-7.48 (m, 3H),

7.39 (1H, t, J = 7.8Hz), 7.16 (1H, qd, J = 6.3.1.5Hz), 1.62-

1.57 (m, 1 H), 1.25-1, 84 (m, 2 H), 0.87-0.81 (m, 2 H). HRMS (MALDI) C 25 H 20 N 4 O 2 [M + H] ⁺ / z calcd 409, 1659, measured

409.1660.

Example 41 (1)

6- [3- ((2-RS-Tris-Phenylcyclopropyl) carbamamido) benzoyl] -3 '- [2- (pyridin-2-yl) ethenyl] -1H-indazole

The compound of Example 41 (1) was prepared in a similar manner to that described in Example 41 (a) except that

273 (IS, 2S) -2-phenylcyclopropanecarboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (CDCl ₃ / MeOD) δ 8.60 (d, 1H, J = 4.2Hz), 8.17 (d, 1H, J =

8.4 Hz), 8.02 (s, 1H), 7.91 (t, 3H, J = 8.1 Hz), 7.78-7.71 (m, 2H), 7.63-7, 56 (m, 3H); 7.47 (t, 1H); 7.32-7.12 (m, 5H);

2.54 (m, 1H), 1.94-1.92 (m, 1H), 1.69 (q, 1H, J = 4.8 Hz), 1.37-1.32 (m, 1H) . HRMS C 31 H 24 N 4 O 2 calculated (M + H ⁺ ) / z 485, 1993, found 485.1995.

Example 41 (m)

6- [3 - ((3-methyl-isoxazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 41 (m) was prepared in a similar manner to that described in Example 41 (a) except that

3-Methylisoxazole-5-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (DMSO-d 6) δ 10.95 (1H, s), 8.68 (1H, d, J 4.2 Hz), 8.44 (d, 1H, J = 8.7 Hz), 8 35 (s, 1 H), 8 / 21-8.18 (m, 1 H), 8.08 (d, 1 H, J =

16.2 Hz), 7.98 (s, 1H), 7.87 (td, 1Η, J = 7.5, 1.8 Hz), 7.76-

7.64 (m, 6H); 7.37-7.33 (m, 1H); 6.72 (s, 1H); 3.36 (s, 3H).

HRMS (MALDI) C ₂₆ H ₁₉ N ₅ O ₃ [M + H ⁺ ] / z: calcd. 450, 1561, measured 450.1570.

Example 41 (n)

274

6- [3 - ((3-tert-butyl-l-methyl-lH-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 41 (n) was prepared in a similar manner to that described in Example 41 (a) except that

5-tert-Butyl-2-methyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ^X H NMR _(CDCl3 / MeOD) δ 8.59 (d, 1 H, J = 4.8 Hz), 8.14 (d, 1 H, J = 8.4 Hz), 8, 08-8, 04 ( m, 1H,), 7.98-7.92 (m, 3H),

7.75 (td, 1H, J = 7.8, 1.8 Hz), 7.68 (dd, 1H, J = 8.4 Hz),

7.61-7.56 (m, 3H), 7.52 (t, 1H, J = 8.70 Hz), 7.25-7.21 (m,

1 H, 6.75 (s, 1 H), 4.12 (s, 3 H), 1.30 (s, 9 H). HRMS (MALDI) C ₃ oH ₂ 0NeO2 [M + ⁺ H] / z Calc'd 505.2347, found 505.2353.

Example 41 (o)

6- [3 - ((5-chlorothien-2-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

The compound of Example 41 (o) was prepared in a similar manner to that described in Example 41 (a) except that

5-Chloro-thiophene-2-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (DMSO-d 6) δ 10.58 (s, 1H), 8.68 (d, 1H, J = 4.2 Hz), 8.43 (d,

1H, J = 8.5Hz), 8.22 (s, 1H,), 8.15 (dt, 1H, J = 7.5, 2.0

8.08 (d, 1H, J = 16.4 Hz), 8.00-7.98 (m, 3H), 7.88 (td,

275

1 H, J = 7.7, 1.9 Hz), 7.78-7.62 (m, 4H,), 7.33 (d, 2H, J = 4.1 Hz). HRMS (MALDI) C ₂₆ H ₁₇ N ₄ O ₂ ClS [M + H ⁺ ] / z: calcd. 485.0843, measured 485.0853.

Example 41 (p)

6- [3 - ((1,3-dimethyl-1H-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

Example 41 (p) was prepared in a similar manner to that described in Example 41 (a) except that

2,5-Dimethyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: Rt 3.90 minutes (100% area). ⁷ H NMR (CDCl ₃ ) δ 8.52 (d,

1H, J = 4.8Hz), 8.10 (d, 1H, J = 8.4Hz), 7.98 (d, 1H, J =

8.1 Hz), 7.93 (s, 1H,), 7.88-7, 80 (m, 3H), 7.71-7.62 (m, 2H), 7.56-7.49 ( m, 4H), 7.44 (t, 1 H, J = 7.8 Hz), 7.16 (dd, 1 H, J =

7.1, 4.8 Hz). HRMS (MALDI) C ₂₇ H ₂₂ N ₆ O ₂ . [M + H ⁺ ] / z: calcd

463.1877, measured 465.1889.

Example 41 (q)

6- [3 - ((2-chloro-6-methyl-pyridin-4-yl) carboxamido) benzoyl] -3-E [2- (pyridin-2-yl) ethenyl] -lH-indazole

Cl

276

Example 41 (q) was prepared in a similar manner to that described in Example 41 (a) except that 2-chloro-6-methylisonicotinic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid . HPLC: Rt 4.11 min (100% area). ^X H NMR (DMSO-de) δ 10.77 (s, 1H), 8.68 (d, 1 H, J = 3.9 Hz), 8.44 (d, 1 H, J = 8.4 Hz); 8.28 (s, 1H), 8.21 (dt, 1H, J = 6.9, 2.1 Hz), 8.08 (d, 1H, J = 16.2 Hz), 7.98 (s 1 H, 7.72-7.64 (m, 9H), 7.35 (dd, 1H, J = 6.6, 4.8 Hz), 2.61 (s, 3H).

Example 41 (r)

6- [3 - ((l-n-propyl-3-methyl-lH-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 41 (r) was prepared in a similar manner to that described in Example 41 (a) except that

5-Methyl-2-propyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid

acid. ^ς Η NMR (DMSO-d 6) δ 10.29 (s, 1H). 8.58 (d, 1H, J = 3.9 Hz) 8.33 (D, 1H, J = 8.4Hz), 8.13 (s, 1 H), 8, 10 (Dt, 1H, J = 5.4, 2.1 Hz) 7.96 (d, 1H, J) = 16.5 Hz), 7, 87 (with, 1H), 7.78 (td, 1H, J = 7.5, 1.5 Hz), 7 , 61-7.49 m 6H), 7 24 (Dd, 1 H, J = 6 of 9 / 1/8 Hz), 4.32 (t, 2H, J = 6.90 Hz) , 1.69 (Q, 2H,

277

J = 7.2 Hz), 0.77 (t, 3H, 7.5 Hz). HRMS (MALDI) C28H20ClN5O2.

[M + H ⁺ ] / z: Calcd. 491.2190, found 491.2203.

Example 41 (s)

6- [3- (4-t-Butylbenzamido) benzyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

Example 41 (s) was prepared in a similar manner to Example 41 (a) except that 4-tert-butylbenzoic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: Rt 4.67 minutes (100% area). 1 H NMR (DMSO) δ 10.45 (s, 1H), 8.44 (d, 1H, J = 8.4

Hz), 8.32 (s, 1 H), 8.22 (d, 1 H, J = 7.5 Hz), 8.07 (d, 1 H, J =

16.5 Hz), 7.99-7.95 (m, 3H), 7.88 (td, 1H, J = 7.7, 1.5 Hz), 7.69-7.59 (m, 7H) 7.38 (dd, 1H, 13.5, 5.1 Hz), 1.36 (s, 9H).

Example 41 (t)

6- [3 - ((1-allyl-3-methyl-1H-pyrazol-5-yl) carboxamido) benzoyl] -3E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

Example 41 (t) was prepared in a similar manner to Example 41 (a) except that 2-allyl-5-methyl-2H-pyrazole-3-carboxylic acid was used instead of 2278 ethyl-5-methyl-2H-pyrazole- 3-carboxylic acid. HPLC: Rt 4.11 min (100% area). ^X H NMR (DMSO) δ 10.46 (s, 1H), 8.74 (t, 1 H, J = 5.1 Hz), 8.48 (d, 1 H, J = 8.4 Hz), 8. 28 (s, 1 H), 8.22 (t, 1 H, J = 5.4, 2.1 Hz), 8.15-8.01 (m, 3 H), 7.39 (td, 1 H, J =

7.8, 1.8 Hz), 7.82-7.63 (m, 6H), 7.39 (td, 1H, J = 7.7, 1.5 Hz), 6.14-6.02 (m, 1H), 5.22-5.03 (m, 4H), 2.38 (s, 3H). HRMS (MALDI) C 29 H 24 N 6 O 2 (M + H ⁺ ) / z: calcd. 489.2034, measured

489.2035.

Example 41 (u)

6- (3 - ((2- chloro-6-methoxy-pyridin-4-yl) carboxamido) benzoyl] -3-E [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 41 (u) was prepared in a similar manner to Example 41 (a) except that 2-chloro-6-methoxy-isonicotinic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R t = 4.37

minutes (100% area). ¹ 1 H NMR (DMSO-d 6) δ 10.74 (s, 1HL r 8, 68 (d, 1H, J = 3.6 Hz), 8.44 (d, 1H, J = 8.4Hz), 8.28 (with, 1H) , 8.20 (td, 1H, J = 6.6, 2.4 Hz), 8.07 (d, 1H, J = 16.2) Hz), r 7, 98 (s, 1H), 7.89 (td, 1H, J) = 7.7, 1.8 Hz), 7.77-7.62 (M, 6H) , 7.38 (s, 1H), 7.35 (dd, 1 H, J = 6.9, 1.8 Hz), 3.98 (s, 3H) •

Example 41 (v)

279

6- (3 - ((3-ethyl-l-methyl-lH-pyrazol-5-yl) carboxamido] benzoyl] -3E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example (v) was prepared in a similar manner to Example 41 (a) except that 5-ethyl-2-methyl

2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. Rt 4.16 minutes (100% area). ^X H NMR _(DMSO-d6) d 10.44 (s, 1H), 8.73 (d, 1 H, J = 3.0 Hz), 8.78 (d, 1H, 8.7 Hz), 8 30 (s, 1H); 8.23 (d, 1H, J = 6.9 Hz); 8.14-8.03 (m, 2H); 7.93 (t, 1H, 6.9 Hz) 7.82-7.63 (m, 6H), 7.40 (t, 1H, J = 6.3 Hz), 7.01 (s, 1H), 4.12 (s, 1H),

2.68 (q, 2H, 7.8 Hz); 1.30 (t, 3H, J = 7.5 Hz). HRMS (MALDI) 2θΗ2 ₄ ββ02 [M + H] ⁺ / z: Calcd. 477.2034, Measured 477.2054.

Example 41 (w)

6- (3 - ((2-chloropyridin-4-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 41 (w) was prepared in a similar manner to Example 41 (a) except that 2-chloroisonicotinic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R t = 3.99 min (100% area). ^X H NMR (DMSO-d ₆₎ δ 10.88 (s, 1H), 7.33 (d, 2H, J = 4.8 Hz), 8.49 (d, 1 H, J = 8.4 Hz) 8.33 (s, 1H); 8.26 (td,

280

1Η, J = 6.9, 3.0 Hz), 8.12-7.91 (m, 5H), 7.82-7.63 (m, 5H),

7.40 (t, 1H, J = 4.8Hz).

Example 41 (x)

6- [3 - ((l-isopropyl-3-methyl-lH-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 41 (x) was prepared in a similar manner to Example 41 (a) except that 2-isopropyl-5-methyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H- pyrazole-3-carboxylic acid. HPLC: Rt

4.19 minutes (100% area). ^X H NMR (DMSO) δ 10.46 (s, 1H), 8.72 (t, 1 H, J = 4.80 Hz), 8.48 (d, 1 H, J = 9.0 Hz), 8. 31 (s, 1 H),

8.21 (td, 1H, J = 9.6, 2.1 Hz), 8.15-7.98 (m, 2H), 7.96-7.84 (m, 1H), 7.82- 7.75 (m, 5H); 7.42-7.38 (m, 1H); 6.88 (s, 1H);

5.64-5.38 (m, 1H), 2.32 (s, 3H), 1.48 (d, 1H, J = 6.6 Hz).

HRMS (MALDI) C 29 H 26 N 6 O 2 [M + H] ⁺ / z, calcd. 491.2190, measured

491.2194.

Example 41 (s)

6- [3- (isopropoxycarbonylamino) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

281

Example 41 (y) was prepared in a similar manner to Example 41 (a) except that isopropyl chloroformate was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (DMSO-d ₆ ) δ 9.97 (s,

1H), 8.72 (t, 2H, J = 4.8 Hz), 8.47 (d, 1H, J = 8.7 Hz), 8.347.96 (m, 3H), 8.01-7 87 (m, 2H); 7.82-7.69 (m, 2H); 7.52 (dt, 1H, J = 7.5, 1.2 Hz); 7.42-7.36 (m) 2H, 3.68 (d, 2H, J = 6.6 Hz), 2.02 (m, 1H), 1.02 (d, 6H, J = 6.6 Hz). HRMS (MALDI)

C26H24N4O3 [M + H] ⁺ / z: Calcd. 441.1921, found 441.1937.

Example 41 (z)

6- [3 - ((4-chloropyridin-2-yl) carboxamido) benzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole

Example 41 (z) was prepared in a similar manner to Example 41 (a) except that 4-chloropyridine-2-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R t = 4.40 min (100% area). ^λ Η NMR (DMSO-d ₆ ) δ 10.99 (s, 1H), 8.72 (d, 1H, J = 5.4 Hz), 8.63 (d, 1H, J = 3.9 Hz) 8.44 (s, 1H), 8.38 (d, 1H, J = 8.4 Hz), 8.25 (dt, 1H, J = 6.6, 2.4 Hz), 8.16 ( d, 1H, J = 1.8 Hz), 8.02 (d, 1H, J = 16.2 Hz), 7.94 (s, 1H), 7.867.80 (m, 2H), 7.72- 7.58 (m, 5H), 7.29 (dd, 1H, J = 6.9, 6.0 Hz).

Example 41 (aa)

282

6- [3- (pyridin-2-ylcarboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 41 (aa) was prepared in a similar manner to that described in Example 41 (a) except that pyridine-2-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (300 MHz, DMF d ₆ ) δ 10.9 (s, 1H), 8.74 (m, 1H), 8.63 (dd, 1H, J = 4.78 Hz, 0.94 Hz), 8.46 (s, 1H), 8.38 (d, 1H, J = 8.48 Hz), 8.25 (dt, 1H, J = 7.17 Hz, J = 2.05 Hz), 16 (dt, 1H, J = 7.73 Hz, J = 1.04 Hz), 8.07 (td, 1H, J = 7.56 Hz, J = 1.67 Hz), 8.02 (d,

1H, J = 16.28 Hz), 7.95 (s, 1H), 7.83 (td, 1H, J = 7.65 Hz, J = 1.81 Hz), 7.22-7.66 ( m, 4H), 7.30 (qd, 1H, J = 7.40 Hz, J = 1.02 Hz). MS (ESI +) [M + H] / z calcd 446, found 446.

Example 41 (bb)

6- [3- (3-methoxybenzamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] indazole-H

Example 41 (bb) was prepared in a similar manner to Example 41 (a) except that 3-methoxybenzoic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3 carboxylic acid. ^Δ NMR (DMSO-d 6) δ 10.50 (s, 1H), 8.67 (d, 1H, J = 3.9 Hz), 8.46 (d, 1H, J = 8.7 Hz), 8.33 (s, 1 H),

8.22 (dt, 1H, J = 7.8, 1.8),

8.08 (d, 1 H, J = 15.0 Hz),

8, 00

283 (s, 1H,), 7.78-7.54 (m, 8H), 7.51 (t, 1H, 7.8 Hz), 7.38-7.33 (m, 1H), 23 (dd, 1H, J = 7.5, 1.5 Hz), 3.90 (s, 3H). HRMS (MALDI) C 29 H 22 N 4 O 3. [M + H] ⁺ / z: Calcd. 475, 1765, found

475.1763.

Example 41 (cc)

6- [3- (fenoxyamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1Hindazol

Example 41 (cc) was prepared in a similar manner to that described in Example 41 (a) except that phenyl chloroformate was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. Mp 212-217 ° C, NMR (300

MHz, DMSO-d 6) δ 13.63 (s, 1H), 10.51 (s, 1H), 8.62 (d, 1H, J =

4.3 Hz), 8.36 (d, 1H, J = 8.6 Hz), 8.04-7.81 (m, 5H), 7.71-

7.40 (m, 7H); 7.31-7.22 (m, 4H). ESIMS m / z 461 [M + H] &lt; ^{+ &gt};. Anal calcd for C 28 H 20 N ₄ O 3 · 0.3 H ₂ O 465.9 g mol ^-1 ): C, 72.18, H, 4.46, N, 11.33. Found: C, 72.41, H, 4.63, N, 1157.

Example 41 (dd)

6- [3- (3,3-dimethylacrylamide) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

284

Example 41 (dd) was prepared in a similar manner to that described in Example 41 (a) except that

3,3-dimethylacrylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ^X H NMR (300 MHz, DMSO-de) δ 13.6 (s, 1H), 10.2 (s, 1H), 8.63 (d, 1H, J = 3.81 Hz), 8.37 ( d, 1H, J = 8.49 Hz), 8.12 (s, 1H), 8.02 (d, 1H, J = 16.34 Hz), 7.99 (d, 1H, J = 7.88) Hz), 7.83 (td, 1H, J = 7.67 Hz, J = 1.78 Hz), 7.70 (d, 1H, J = 7.85 Hz), 7.63 (dd, 1H, J =

8.43 Hz, J = 1.23 Hz), 7.47-7.56 (m, 2H), 7.29 (qd, 1H, J =

7.39 Hz, J = 0.99 Hz), 6.82 (m, 1H, J = 6.9 Hz), 5.85 (s, 1H),

2.12 (s, 3H), 1.85 (s, 3H). MS (ESI +) [M + H] / z vypočítané409, found 409. Anal calcd for C 6 H ₂₂ N ₂ O ₄ · ₂ 0.33 TBME: C,

H, 5.80; N, 12.41. Found: C, 73.26, H, 5.76, N, 12.36.

Example 41 (ee)

6- (3 - ((l-ethyl-3-methyl-lH-pyrazol-5-yl) carboxamido) -4metylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

example from

Compound (ee) was prepared in a similar manner to Example (a) except that the compound was from Example 40 (b) (a). 1 H NMR (DMSO-d 6) used in place of Example δ 13.6 (S, 1H),

9.94 (s, 1 H)

8.62 (d,

1H, J = 3.8Hz), 8.36 (d, 1H,

J = 8.51

Hz), 8.01 (d,

1H, J

16.36 Hz),

7.91 (s, 1 H)

7.84 (dd, 1 H,

J = 7.66 Hz,

J = 1.74

Hz), 7.81 (s, 1H), 7.70 (d, 1H, J = 7.9)

Hz), 7.64 (d,

1H, J

16.45 Hz),

7.62 (m. 2H)

7.29 (m,

1H), 6.82 (s, 1H), 4.42 (q, 2H, J = 7.06 Hz), 2.36 (s, 3H),

285

2.21 (s, 3H), 1.30 (t, 3H, J = 7.09 Hz). MS (ESI +) [M + H] / z calcd 491, found 491. Anal. Calcd: C, 71.00, H, 5.34, N, 17.13. Found: C, 70.80, H, 5.38, N, 17.00.

Example 41 (ff)

6- [3 - ((l-allyl-3-methyl-lH-pyrazol-5-yl) carboxamido) -4metylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 41 (ff) was prepared in a similar manner to that described in Example 41 (ee) except that

2-Allyl-5-methyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ^X H

NMR (DMSO-de) δ 13.6 (s, 1H), 9.9 8 (p , 1H), 8.62 (d, 4, 60 Hz), 8.36 (d, 1H, J = 8.46 Hz), 8.01 (d, 1H, Hz), 7.91 (s, 1H), 7.83 (td, IH, J = 7.69 Hz, J = 7.78 (d, 1H, J = 1.73) 7.70 (d, IH, J = 7.78 Hz) (M, 3H), 7.50 (d, 1H, J = 8.01 Hz) , 7, 29 (qd, 1 H, J = J = 1.02 Hz), 6.86 (s, 1H), 5.95 (M, 1H), 4.93-5.10

7.59 to 7.70

7.46 Hz,

3H);

J = 16.37

3H). LCMS (ESI &lt; + &gt;), IH, J

2.22 (s, (m, 4H), [M + H] / z calcd

503, measured 503. Anal.

Calculation: C, 71.70,

H, 5.21; N, 16.72.

Found: C, 70.98, H, 5.42, N, 15.94.

Example 41 (gg)

6- (3-acetamido-4-methyl-benzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] indazole-H

286

The compound of Example 41 (gg) was prepared in a similar manner to that described in Example 41 (ee) except that acetyl chloride was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (CD ₃ OD) δ 8.57 (d, 1H, J = 4.90 Hz), 8.13 (d, 1H, J = 8.49 Hz), 7.99 (s, 1H), 7.95 (d, 1H, J = 16.53 Hz), 7.89 (d, 1H, J = 1.46 Hz), 7.86 (td, 1H, J = 7.64)

Hz, J = 1.73 Hz), 7.73 (d, 1H, J = 7.05 Hz), 7.62-7.69 (m, 2H), 7.65 (d, 1H, J = 16 Hz) 48 Hz) 7.44. (d, 1H, J = 7.97Hz),

7.32 (qd, 1H, J = 7.44 Hz, J = 1.03 Hz), 2.38 (s, 3H), 2.18 (s, 3H). LCMS (ESI +) [M + H] / z calc. 397, measured 397. Anal. Calcd: C, 72.71, H, 5.08, N, 14.13. Found: C, 72.29; H, 5.09; N, 13.98.

Example 41 (hh)

6- [3 - ((1,3-dimethyl-lH-pyrazol-5-yl) carboxamido) -4-methyl-benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 41 (hh) was prepared in a similar manner to that described in Example 41 (ee) except that

2,5-Dimethyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: R t = 3.92 min (100% area). ^X H NMR (DMSO) δ 10.02 (s, 1H), 8.74 (d, 1 H, J = 3.6 Hz), 8.49 (d, 1 H, J = 8.4 Hz), 8. 13

287 (d, 1H, J = 16.3 Hz), 8.03 (s, 1H), 7.96-7.93 (m, 2H), 7.84-

7.72 (m, 4H), 7.63 (d, 1H, 8.1 Hz), 7.42 (dd, 1H, J = 6.8, 1.5 Hz), 6.95 (s, 1H ), 4.11 (s, 1H), 2.48 (s, 1H), 2.32 (s, 1H).

Example 41 (ii)

6- [3 - ((l-n-propyl-3-methyl-lH-pyrazol-5-yl) carboxamido) -4metylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 41 (ii) was prepared in a similar manner to that described in Example 41 (ee) except that

5-Methyl-2-propyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. HPLC: Rt 4.16 min (100% area). ^X H NMR (DMSO-de) δ

10.29 (s, 1H), 8.58 (D, IH, 3, 9 Hz), 8.33 (d, 1H, J = 8.4 HZ), 8.13 (s, 1H), 8.10 (Dt, IH, J = 5.4, 2.1 Hz), 7.96 (d, 1H, J = 16, 5 Hz), 7.87 (s, IH) 7.78 (td, IH, J = 7 5, 1.5 Hz), 7 , 61- 7.49 (m, 6H) 7.24 (Dd, IH, J = 6.9, 1.8 Hz), 4.32 (t, 2 H, J = 6, 90 Hz), 2.58 (s, 3H) , 2.22 (s, 3H) 1.69 (q, 2H, J = 7.2 Hz), 0.77 (t, 3H, 7.5 Hz). HRMS (MALDI) &lt; tb &gt; 0θΗ26Νβθ2. [M + H ⁺ / z:

calcd. 505.2347, found 505.2343.

Example 41 (jj)

6- [3 - ((3-ethyl-1-methyl-1H-pyrazol-5-yl) carboxamido) -4-methylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] - H-indazole

288

Example 41 (jj) was prepared in a similar manner to that described in Example 41 (ee) except that

5-Ethyl-2-methyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (DMSO-d 6) δ 10.78 (s, 1H), 9.43 (d, 1H, J = 3.0 Hz), 9.15 (t, 1H, J = 9.6 Hz), 8.82 (dd, 1H, J = 16.4, 1.5 Hz), 8.72-

8.61 (m, 2H), 8.52-8.30 (m, 4H), 8.10 (dd, 1H, J = 6.9, 5.7), 7.93-7.89 (m (1H), 7.72-7.69 (m, 1H), 4.85 (s, 3H), 3.39 (q, 2H, J = 7.8 Hz), 3.17 (s, 3H) 2.10 (t, 3H, J = 7.5Hz). HRMS (MALDI) C 29 H 26 N 6 O 2 (M + H ⁺ ) m / z: calcd. 491.2190, measured

491.2211.

Example 41 (kk)

6- [3 - ((1-Isopropyl-3-methyl-1H-pyrazol-5-yl) carboxamido) -4-methylbenzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H- indazole

Example 41 (kk) was prepared in a similar manner to that described in Example 41 (ee) except that 2-isopropyl-5-methyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5- methyl-2H-pyrazole-3-carboxylic acid. HPLC: Rt 4.11 min (100% area). ^X H NMR (DMSO-d ₆₎ δ

289

9.99 (s, 1H), 8.68 (d, 1H, J = 3.6Hz), 8.42 (d, 1H, J = 8.7)

Hz), 8.07 (d, 1H, J = 16.4 Hz), 7.98 (s, 1H), 7.67-7.86 (m,

2H), 7.77-7.65 (m, 4H), 7.56 (d, 1H, J = 7.8 Hz), 7.37-7.33 (m, 1H), 6.82 (s (2H), 5.44-5.36 (m, 1H), 2.42 (s, 3H), 2.28 (s, 3H), 1.42 (d, 6H, J = 6.6 Hz) . Anal. (C ₃₀ H ₂₈ N ₆ O ₂ 0.2H ₂ O) calculated: C, 5.63, N, 16.54. Found: C, 70.57; H, 5.70; N, 16.35.

Example 41 (11)

6- [2,4-Dimethyl-5 - ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

the example was used

41 (a) except

of Example 40 as in Example 40 (c) (a). ⁷ H NMR (DMSO-d 6) prepared by a similar compound δ 13.6 (d, 1H, instead of the compound of Example (s, 1H), 9.82 (s, 1H)

8.63 (d,

J = 8.54 Hz), 8.00 (d,

1H, J

16.37 Hz), 7.83 (s, 1H), 7.83 (td, 1H, J = 7.65 Hz, J = 1.82)

Hz), 7, 69 (d, ll H, J = 7.89 Hz), 7, 65 (dd, 1 H, J) = 8.52 Hz, J = 1.36 Hz), 7.62 (D, 1H, J = 16.34 Hz), 7.35 (s, 1H), 7.32 (s, 1 H>. 7-, 2 9 (Qd, 1H, J = 7.42 Hz · J = 1.09 Hz), 6.78 - (s, 1H) -, 4.39 (Q, 2H, J = 7 15 Hz), 2.30 (S, 3H) 2.25 (s, 3H) 2.19 (with, 3H), 1.27 (T, 3H, J = 7.1 5 Hz). LCMS (ESI +) [M + H] / z

calculated 505, measured 505.

Example 41 (mm)

6- [2,4-dimethyl-5 - ((1,3-dimethyl-lH-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH indazol

290

Example 41 (mm) was prepared in a similar manner to that described in Example 41 (11) by creaming

2,5-Dimethyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (DMSO-d 6) δ 13.6 (s, 1H), 9.81 (s, 1H), 8.62 (d, 1H, J =

3.81 Hz), 8.35 (d, 1H, J = 8.6 Hz), 8.00 (d, 1H, J = 16.36 Hz), 7.83 (dt, 1H, J = 7, 65 Hz, J = 1.8 Hz), 7.8 (s, 1H), 7.69 (d, 1H, J = 7.88 Hz), 7.65 (dd, 1H, J = 8.53 Hz) , J = 1.36 Hz),

7.62 (d, 1H, J = 16.35 Hz), 7.36 (s, 1H), 7.32 (s, 1H), 7.29 (qd, 1H, J = 7.41 Hz, J = 1.03 Hz), 6.79 (s, 1H), 3.96 (s, 3H), 2.30 (s, 3H), 2.25 (s, 3H), 2.18 (s, 3H) ). LCMS (ESI +) [M + H] / z calcd 491, found 491. Anal. Calcd: C, 71.00, H, 5.34, N, 17.13. Found: C, 70.69, H, 5.57, N, 16.26.

Example 41 (nn)

6- (5-acetamido-2,4-dimethyl-benzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 41 (nn) was prepared in a similar manner to that described in Example 41 (11) except that acetyl chloride was used in place of 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid. ¹ H NMR (DMSO-d ₆ ) δ 13.6 (bs, 1H),

291

9.34 (s, 1H), 8.62 (d, 1H, J = 4.15 Hz), 8.33 (d, 1H, Hz), 7.86 (d, 1H, J = 16.36 Hz) 7.83 (td, 1H, J = 7, = 1.82 Hz), 7.81 (s, 1H), 7.69 (d, 1H, J = 7.84 Hz), 1H, J = 1.38 Hz), 7.62 (d, 1H, J = 16.46 Hz), 7.48 (s, (qd, 1H, J = 7.44 Hz, J = 1.02 Hz), 7 24 (s, 1H), 3H), 2.23 (s, 3H), 2.02 (s, 3H). LCMS (ESI +) calcd 411, found 411.

Examples 41 (oo) -41 (111) can be prepared

J = 8.67 Hz, J ', 64 (dd, H), 7.29 2.27 (s, [M + H] / z in a similar manner to that described in Example 41 (a).

Example 41 (oo)

Example 41 (pp)

Example 41 (qq)

292

Example 41 (rr)

Example 41 (ss)

Example 41 (tt)

Example 41 (uu)

293

Example 41 (w)

Example 41 (ww)

Example 41 (xx)

Example 41 (yy)

294

Example 41 (zz)

Example 41 (aaa}

Example 41 (bbb)

Example 41 (ccc)

Example 41 (ddd)

295

Example 41 (eee)

Example 41 (fff)

Example 41 (ggg)

Example 41 (hhh)

Example 41 (iii)

Example 41 (jj j)

Example 41 (kkk)

296

Example 41 (111)

297

Example 42 (a)

6- (3-Benzamidobenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

0.58 g (80.6%) of Example 42 (a) was prepared from 6- (3-benzamidobenzoyl) -3-E- [2- (pyridin-2-yl) ethenyl] -1- (2-trimethylsilanylethoxymethyl) 1 H-indazole similar to Example 12. HPLC 4.13 minutes (98% area). ^{Χ Η} NMR (CDC1 ₃₎ δ

8.66 (d, 1H, J = 4.1 Hz), 8.24 (d, 1H, J = 8.5 Hz), 8.11-8.10 (m, 3H), 8.01-7 98 (m, 4H), 7.83 (t, 2H, J = 7.1 Hz), 7.72-

7.53 (m, 7H), 7.30 (qd, 1H, J = 52, 1.1 Hz). HRMS (MALDI) C 28 H 20 N 4 O 2. [M + H ⁺ ] / z: Calcd. 445, 1664, found 445, 1659.

Anal. (C 26 H 19 N 5 O 2 · 0.2 EtOAc): C, 75, 87, H, 4.78, N, 12.39.

The starting material was prepared as follows:

(I)

To a stirred solution of 4.00 g (8.40 mmol) of 6-iodo-3 ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazole

298 of Example 14, step (i), in 48 mL of anisole under argon, 176 mg (0.25 mmol) of bis (triphenylphosphine) palladium dichloride, 288 mg (1.0 mmol) of TBACI, 1.54 mL (16, 8 mmol) of 2-butanol and 3.48 g (25.2 mmol) of potassium carbonate. The resulting mixture was stirred under a carbon monoxide atmosphere at 80 ° C for 100 hours. After removal of the solvent by concentration in vacuo, the residue was diluted with 400 mL EtOAc and extracted with 2 x 150 mL saturated NaCl, 2 x 50 mL saturated NaHCO 3, and 2 x 50 mL water, then the organic layer was filtered through 20 mL silica gel. The organic filtrate was then concentrated in vacuo to give an amber oil. Purification by flash chromatography from hexane / EtOAc (7: 3) gave 2.38 g (61% yield) of 6 (3-aminobenzoyl) -3 - ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) - 1H-indazole as an amber oil. ^X 1 HNMR (CDCl ₃₎ δ 8.84 (dd, 1H, J = 8.70, 0, 90 Hz), 8.02 (s, 1H), 7.77 (dd, 1 H, J =

8.40, 1.50 Hz), 7.62-7.59 (m, 2H), 7.40 (t, 2H, J = 7.20 Hz), 7.38-7.24 (m, 4H) 7.22-7.19 (m, 3H), 6.98 (dq, 1H, J = 8.30,

0.90 Hz), 3.83 (bs, 2H), 3.61 (t, 2H, J = 8.10 Hz), 0.91 (t, 2H, J = 7.20 Hz), 0.17 (s, 9H).

(Ii)

To a stirred solution of 3.22 g (6.87 mmol) of 6- (3-aminobenzoyl) 3- ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) -ΙΗ-indazole in 10 mL of methylene chloride under argon was added 0 , Benzoyl chloride (95 mL, 8.37 mmol) and pyridine (0.67 mL, 3.22 mmol). After 2 hours, the solution was diluted with 100 mL EtOAc and washed with 1 x 50 mL saturated NaCl, 2 x 50 mL citric acid (1M, pH)

299

2.5) and 2 x 50 mL of a mixture of NaHCl 3 and water (50:50). The organic layer was dried over Na 2 SO 4 and filtered through 20 mL of silica gel. The organic layer was concentrated in vacuo to give the product as a yellow solid. Purification using flash chromatography on silica gel eluting with hexane / EtOAc (7: 3) gave 3.22 g (85.1% yield) of 6- (3-benzamidobenzoyl) -3- ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) -ΙΗ-indazole as a yellow foam. ¹ H NMR (CDCl ₃ ) δ 8.19 (d, 1H, J = 8.7 Hz), 8.16 (s, 1H,), 8.11-8.10 (m, 2H), 8.03 -7.93 (m, 3H), 7.82 (dd, 1H, J = 8.4, 1.2 Hz), 7.70-7.67 (m, 3H),

7.44 (m, 5H), 7.48 (t, 2H, J = 14.1 Hz) 7.39 (1H, d, J

7.2 Hz).

(Iii)

Stirred solution 2.35 g (4.07 mmol) of 6- (3-benzamidobenzoyl) -

3 - ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazole in 45.6 ml methylene chloride was cooled to -45 ° C using a bath with a mixture of acetonitrile and solid carbon dioxide. Ozone was then bubbled through the solution at a rate of 1.5 L / m, 60 A for 15 minutes. The reaction mixture was quenched by the addition of 2.5 mL of hydrogen sulfide and warmed to 25 ° C. The methylene chloride was removed by concentration in vacuo. The residue was purified on silica gel eluting with hexane / EtOAc (7: 3) to give 1.74 g (85% yield) of 6- (3-benzamidobenzoyl) -1 (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carboxaldehyde as off-white foam. HPLC 3.78 minutes (100% area), ¹ H NMR (DMSO-d 6) δ 10.77 (s, 1H), 10.42 (s, 1H), 8.46-8.39 (m, 2H) 8.31 (dt, 1H, J = 6.0, 1.8 Hz), 8.19 (s, 1H,), 8.11-8.07 (m,

300

2 δ, 7.91 (dd, 1H, J = 6.0, 1.2 Hz), 7.70-7.64 (m, 5H), 5.81 (s, 2H) 3.68 (t (2H, J = 6.9Hz),

0.98 (t,

2H, J = 6.7Hz)

0.02 (s, 9H).

(Iv)

To a stirred solution of 2.23 g (4.91 mmol)

Of 2-picolytriphenylphosphonium chloride / sodium hydride cooled to -78 ° C was added 1.26 g (2.46 mmol) of 6- (3-benzamidobenzoyl) - (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carboxaldehyde in 5 mL of anhydrous THF under argon and the solution was stirred for 1 hour at 0 ° C and quenched with CH ₃ COOH and

MeOH (1: 1.1 mL). The reaction mixture was diluted with 100 mL EtOAc and partitioned between 1 x 50 mL saturated NaCl and 2 x 50 mL saturated NaHCO 3, then the organic layer was dried over Na ₂ SO ₄ and filtered through a short column of 20 mL silica gel (trans / cis 3: 1). ). Purification on a 4 mm silica gel round plate eluting with hexane / EtOAc (1: 1) gave a concentration of 1.05 g (62%) of 6- (3-benzamidobenzoyl) -3-E- [2 (pyridin-2-yl)]. ) ethenyl] -1- (2-trimethylsilanyl-ethoxymethyl) -lH-inda-

Zola than yellow solid. ^X H NMR (CDCl 3) δ 8.62 (D, 1H, J = 4.1 Hz); 8.22 (d, 1 H, J = 8) 5 Hz), 8, ´11 -8.10 (m, 3H ), θ , 01- 7, 98 (M, 4H), 7.83 (t, 2 H, J = 7.1 Hz), 7.72-7, 53 (M, 7 H); 7.30 (Qd, 1H, J = 5.2, 1.1 Hz ) 5.81 (s, 2H); 3.68 (T, 2H, J = 6, 9: Hz); 0, 98 (t, 2H, J = 6.7) Hz ), 0.02 (s, 9H).

Example 42 (b)

6- (3-Benzamidobenzoyl) -3- (1H-benzimidazol-2-yl) -1H-indazole

301

The compound of Example 42 (b) was prepared in a similar manner to that described in Example 42 (a) except that step (iv) was replaced by the following: to the aldehyde prepared in Example 42 (a), step (iii) was added 0.011 g (0.11 mmol)

1,2-diaminobenzene, 0.4 g (0.1201 mmol) elemental sulfur, (US pharmacopoeial purity), 2 mL anhydrous DMF, and the mixture was heated to 90 ° C for 18 hours and cooled to 25 ° C. The reaction mixture was diluted with 10 mL ethyl acetate and washed with 1 x 10 mL saturated NaCl, 1 x 10 mL NaHCO 3, and 10 mL water, dried over Na ₂ SO _4, and filtered through a 0.22 μΜ Teflon filter and concentrated to give an amber oil. Purification by circular plate chromatography followed by precipitation from 2 mL of methylene chloride and 2 mL of hexane gave the intermediate as a white precipitate. ¹ H NMR (acetone-de) δ 8.81 (d, 1H, J = 8.6),

8.30-8, 25 (m, 2H), 8.11 (s, 1H), 8.02-7.99 (m, 2H), 7.79 (td, 2H, J = 12.2, 1) 2 Hz), 7, 63-7, 47 (m, 7H), 7.28-7, 40 (m, 2H). HRMS (MALDI) m / z C _{2 e} Hi9N ₅ O 2 Calculated (M + H ^+): 458, 1617, found 458.1632.

Example 42 (c)

6- (3-Benzamidobenzoyl) -3-E- [2- (2-methylthiazol-4-yl) ethenyl] -1H-indazole

302

The compound of Example 42 (c) was prepared in a similar manner to that described in Example 42 (a) except that

4- (2-methylthiazyl) methyltriphenylphosphonium chloride was used in place of 2-picolytriphenylphosphonium chloride in step (iv). ¹ H NMR (DMSO) δ 8.11-8.01 (m, 4H), 7.92 (d, 2H, J = 6.9 Hz), 7.76-7.71 (m, 2H), 7 65-7.62 (m, 1H); 7.56-7.48 (m, 5H); 7.15 (s, 1H);

2.81 (s, 3H). HRMS (MALDI) C 27 H 20 N 4 O 2 S [M + H ⁺ ] / z: calcd (M + H ⁺ ) 465, 1380, found 465, 1373.

Example 42 (d)

6- (3-Benzamidobenzoyl) -3- (3 H -imidazo [4,5- b] pyridin-2-yl) -1Hindazol

Example 42 (d) was prepared in a similar manner to Example 42 (b) except that 1,2-diamine-2-pyridine was used instead of 1,2-diaminobenzene. HPLC: 3.88 minutes (95% area), ¹ H NMR (DMSO-d 6) δ 10.62 (s, 1H), 8.83 (d, 1H, J = 8.4 Hz), 8.53 ( s, 1H); 8.43 (s, 1H); 8.32 (dt, 1H, J =

6.9, 1.8 Hz), 8.15 (d, 1H, J = 12.9 Hz), 8.11-8.10 (m, 2H),

7.91 (d, 1H, J = 9.0 Hz), 7.72-7.65 (m, 6H), 7.43 (dd, 1H, J = 6.3, 4.5 Hz). HRMS (MALDI) m / z C 27 H 18 N 6 O 2 calculated (M + H ⁺ ):

459, 1564, measured 459, 1558. Anal. (C 27 H ₈ N ₆ O ₂ · 0.4 CH ₂ C1 _2):

C, 66.83; H, 3.85; N, 17.07. Found: C, 66.93, H, 4.04, N, 16.68.

303

Example 42 (e)

6- (3-Benzamidobenzoyl) -3-E- [N- (4H-1,2,4-triazol-4-yl) iminomethyl] -1H-indazole

Example 42 (e) was prepared in a similar manner to Example 42 (a) except that 4-amino-1,2,4-triazole and PPTS were used at 80 ° C instead of 2-picolytriphenylphosphonium chloride / potassium hydride at 23 ° C. HPLC: R t = 4.05 min (96% area), ³ H NMR (DMSO-d 6) δ 10.58 (s, 1H),

9.53 (s, 1 H), 9.40 (s, 2 H), 8.56 (d, 1 H, J = 8.4 Hz), 8.38 (s, 1 H), 8.26 (dt, 1 H) J = 7.2, 2.1 Hz), 8.13 (s, 1H), 8.08-8.05 (m, 2H), 7.73-7.67 (m, 5H). HRMS (MALDI) C ₂₄ H ₁₇ N ₇ O 2 [M + H ⁺ ] / z.

Calculated 436, 1516, measured 436, 1510. Anal. (C 24 H 17 N 7 O 2 · 0.4 hexane) calcd C, 66.18, H, 4.67, N, 20.47. Found: C, 65.78, H, 4.87, N, 20.47.

Example 43

6- (3-Benzamidobenzoyl) -3-E- [2- (2-formamidophenyl) ethenyl] -1H-indazole mg (36%) of Example 43 was prepared from 6 (3-benzamidobenzoyl) -3-E- (2- formamidophenyl) ethenyl-1- (2-trimethylsilanylethoxymethyl) -ΙΗ-indazole in a similar way as

304 was described in Example 11. HPLC: R t = 4.19 min ¹ H NMR (CDCl ₃ ) δ 8.43-7.92 (m, 6H), 7.68-7.49 (m, 4H) 7, 39-7,36 (m,

3H), 7.32-7.21 (m, 2H), 7.09-7.00 (m, 2H), 6.91-6.84 (m, 1H).

HRMS (MALDI) C 30 H 22 N 4 O 3 [M + Na] / z: calcd. 509, 1590, found 509, 1580. Anal. (C30H22N4O3 · 0.3H2O) calculated: C, 73.25, H,

4.63, N, 11.39. Found: C, 73.10, H, 4.58, N, 11.28.

The starting material was prepared as follows:

(I)

6- (3-benzamidobenzoyl) -1- (2-trimethylsilanylethoxymethyl) -1Hindazole-3-carboxaldehyde (prepared in Example 42 (a), step (iii)) was converted to 6- (3-benzamidobenzoyl) -3-E- (2-nitrophenyl) ethenyl-1- (2-trimethylsilanylethoxymethyl) 1H-indazole in a similar manner to Example 42 (a), step (iv) except that (2-nitrobenzyl) triphenylphosphonium bromide monohydrate was used in place of 2-picolytriphenylphosphonium chloride (0) 19 g (79%). ³ H NMR (CDCl 3) δ 8.15-7.93 (m, 5H), 7.89-7, 86 (m, 3H), 7.54-7.41 (m, 6H), 7.36- 7.35 (m,

2H), 7.21-7.18 (m, 2H), 7.03-6.91 (m, 1H), 3.64-3.46 (m, 2H),

0.96-0.79 (m, 2H), -0.06 (s, 9H).

(Ii)

305

0.19 (0.32 mmol) of 6- (3-benzamidobenzoyl) -3-E- (2-nitrophenyl) ethenyl-1- (2-trimethylsilanylethoxymethyl) -ΙΗ-indazole was dissolved in 3 mL of DMF treated with 0, 26 g (1.40 mmol) of SnCl ₂ and 0.037 mL (1.87 mmol) of water were stirred for 3 hours at 50 ° C. The reaction was stopped at 25 ° C with 0.5 mL of 3N NaOH and the precipitate was removed by filtration through celite. The solution was then partitioned between 2 x 30 mL of saturated NaHCO 3 and water (50/50) and the organic layer was filtered through a short silica gel column to give 0.17 g (92%) of 6- (3-benzamidobenzoyl) -3-E ( 2-aminophenyl) ethenyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole as an amber oil. The product was used without further purification.

0.17 (0.28 mmol) of 6- (3-benzamidobenzoyl) -3-E- (2-aminophenyl) ethenyl-1- (2-trimethylsilanylethoxymethyl) -ΙΗ-indazole was dissolved in 3 ml of methylene chloride. To this solution was added dropwise 0.12 g (0.56 mmol) of formic acid pentafluorophenyl ester. After 3 hours, the reaction mixture was diluted with 40 mL EtOAc and washed with 2 x 30 mL 50/50 NaHCO _3, and the organic layer was filtered through a short column of silica gel. The residue was purified by ring-plate chromatography on silica gel, eluting with hexane / EtOAc and CH ₂ Cl ₂ (1: 1: 1) to give 63 mg (40%) of 6- (3-benzamidobenzoyl) -3-E- (2formamidophenyl) Ethenyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole as a clear oil. ¹ H NMR (CDCl 3) δ δ, 48-8.36 (m, 1H),

8.20-7.84 (m, 4H), 7.61-7.52 (m, 5H), 7.41-7.32 (m, 4H), 7.26306

7.01 (m, 4H), 6.82 (t, 1H, J = 14.2 Hz), 3.48-3.23 (m, 2H),

0.95-0.87 (m, 2H); -0.05 (s, 9H).

Example 44

6- (3-aminobenzoyl) -3-E- [N- (pyrrol-l-yl) iminomethyl] -lH-indazole

Example 44 was prepared from the starting material described below in a similar manner to that described in Example 12. R _f sm 0.6, p 0.5 (ethyl acetate): ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.8 (s, 1H), 8.5 (d, 1H), 7.95 (s, 1H), 7.75 (d, 1H), 7.45-7.3 (m, 7H), 7.2 ( m, 1H), 6.40 (s, 2H).

The starting material was prepared as follows: (i)

204 mg (0.507 mmol) of the aldehyde prepared in Example 33 (a), step (i), and 67 μΐ (0.66 mmol, 1.3 eq) of 1-aminopyrrole were stirred together in 2 mL of toluene. To this mixture was added 1 mg of PPTS and the solution was heated to 80 ° C for 1 hour. The mixture was cooled and partitioned between a 2: 8 mixture of ethyl acetate and hexane and water. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure. 215.7 mg (91%) of the product was crystallized from 0.5 mL of dichloromethane and 2 mL of methanol: ¹ H NMR (300 MHz, C ₆ D ₆ ) δ 8.71 (s,

307

1 H), 8.25 (d, 1H, J = 8.5 Hz), 8.08 (s, 1H), 7.75 (d, 1H, J

8.5 Hz), 6.35 (s, 2H), 5.85 (s, 2H).

(Ii)

IN A mixture of 535 mg (1.15 mmol, 1 eq) of the above iodide, 236 mg (1.72 mmol, 1.5 eq.) Of 3-aminophenylboronic acid, 24 mg (0.034 mmol, 0.03 eq.) PdCl ₂ (PPh 3) 2 and carbonate

potassium carbonate was taken up in 6.7 ml of anisole under an atmosphere of carbon monoxide, 1 atm. The mixture was heated to 80 ° C for 14 hours. The mixture was cooled, partitioned between ethyl acetate and water. The organic layers were washed with saturated aqueous sodium bicarbonate, water and brine, and the organic layer was separated. The organic material was dried over sodium sulfate, decanted and concentrated under reduced pressure. Purification by silica gel chromatography (50 mL silica gel, ethyl acetate / hexane 2: 8 to 3: 7) gave 331 mg (63%) of aniline as a solid: R f sm 0.60, p 0.21 (ethyl acetate / hexane 3: 7), ^X H NMR (300 MHz, CDCl3) δ 8.75 (s, 1H), 8.51 (d, 1 H, J = 8.4 Hz), 8.06 (s, 1H), 7.76 (dd, 1H, J = 1.3, 8.4 Hz), 7.26 (m, 3H), 7.17 (m, 2H), 6.92 (m, 1H), 6.31 (t, 1H, J = 2.3 Hz), 5.79 (s, 2H), 3.84 (br s, 2H), 3.60 (t, 2H, J = 8.2 H _2), 0.91 ( t, 2H, J = 8.2 Hz), -0.08 (s, 9H). LCMS

4.98 minutes (pos) [M + H] / z calcd 460, measured 460.

Example 45 (a)

308

6- [3- (indol-4-ylcarboxamido) benzoyl] -3-E- [N- (pyrrol-1-yl) iminomethyl] -lH-indazole

The compound of Example 45 (a) was prepared according to Example 44 in a similar manner to that described in Example 12 (d) except that the indole-4-carboxylic acid was used instead.

5-methyl-thiazole-2-carboxylic acid: _Rf sm 0.0, p 0.2 (ethyl acetate-benzene 1: ^3), IH NMR (300 MHz, DMSO-d₆) δ 9.84 (s, 1H) 8.92 (s, 1H), 8.66 (s, 1H), 8.39 (d, 1H, J = 8.5 Hz), 8.02 (s, 1H), 7.86 (m, 2H), 7.66 (d, 1H, J = 8.5Hz), 7.52-

7.40 (m, 4H), 7.27-7.07 (m, 5H), 6.83 (s, 1H), 6.21 (s, 2H).

Example 45 (b)

6- (3-Benzamidobenzoyl) -3-E- [N- (pyrrol-1-yl) iminomethyl] -1H-indazole

The compound of Example 45 (b) was prepared in Example 44 in a similar manner to that described for Example 12 (d), except that benzoyl chloride was used instead of 5-methylthiazole-2-carboxylic acid and HATU: ^X H NMR (300 MHz, CDCl 3, Δ 11.9 (bs, 1H), 8.70 (s, 1H), 8.43 (s, 1H), 8.39 (d, 1H, J = 8.4 Hz), 7.99 (s) s, 1H), 7.9-7.8 (m, 4H), 7.65 (d, 1H, J = 8.4 Hz),

309

7.48 (t, 2H, J = 7.8Hz), 7.42-735 (m, 3H), 7.20 (t, 2H, 2.2)

Hz), 6.28 (t, 2H, J = 2.2 Hz).

Example 46

6- [N- (3-aminophenyl) amino] -3-E-styryl-lH-indazole

Example 46 was prepared from the starting material similar to ² H NMR (300 described below in Example 13 (i)).

8.07 (s, 1H).

7.77 (d, 1H, J)

6, 44

7.88 i

7.40 (m, (t, 1H, by the method of

MHz, _DMSO-d6)

8, 73 Hz), 7.69 was

7.28 (m, 1H); 7.06 (d, 1H, J)

J = 1.98 Hz) (bs, 2H).

Compound prepared in Example 11 described δ 12.6 (d, 1H,

(WITH, 1H), J = 8, 49 1.49 Hz), 1H, J =

step (v), was converted to 6- [N- (3-nitrophenyl) amino] -3-E-styryl-lH-indazole in a similar manner to that described for Example ^{12; H} NMR (300 MHz, CDC1 ₃₎ δ 8.0 (m, 2H), 7.77 (m, 1H), 7.64 (d, 2H, J = 7.86 Hz), 7.41-7.56 (m, 6H), 7, 33 (m, 2H), 7.08 (d, 1 H, J =

8.67 Hz). MS (ESI +) [M + H] / z calc. 357, measured 357. Calculated: C, 70.77, H, 4.53, N, 15.72. Found: C, 69.18; H, 4.51; N, 15.30.

310

Example 47

6- [N- (3-Benzamido-4-fluorophenyl) amino] -3-E-styryl-1H-indazole

6- [N- (3-benzamido-4-fluorophenyl) amino] -1- (2-trimethylsilanylethoxymethyl-3-E-styryl-1H-indazole) was converted to the compound of Example 47 in a similar manner to that described in Example 11. ^X H NMR (300 MHz, _DMSO-d6) δ 12.6 (s, 1H), 10.0

(S, 1 H), 8.38 (w, 1H) 8.02 (d, 1 H, J = 8.78), 7, 98 (d, 2H, J = 6.87 Hz), 7.69 (D, 2H, J = 7.27 Hz), 7.48-7.61 (m, 4H), 7.45 (s, 2H), 7.40 (T, 2H, J = 7.28 Hz), 7.53-7.30 ( t, 2H, J = 7.28 Hz), 7.53 to 7.30 m. 2H), 7.07 (d, 1H, J = 1.55 Hz), 7.03 (m, 1 H), 6.95 (dd, 1H, J = 8.79 Hz, J = 1.85 Hz). MS (ESI +) [M + H] / z calcd. 449, measured 449. Anal, calculation: C, 74 , 98th

H, 4.72. N, 12.49. Found: C, 74.29. H, 4.76. N, 12.12.

The starting material was prepared as follows:

(I)

To a solution of 3.12 g (20 mmol) of 2-fluoro-5-nitrophenylamine in 20 mL of dichloromethane at 23 ° C under argon was added

1.94 ml (24 mmol) of pyridine and 2.8 ml (24 mmol) of benzoyl chloride. After 45 minutes a white precipitate formed. The reaction mixture was concentrated in vacuo, then diluted with water and filtered to give a white solid, which was resuspended in MeOH and filtered again to give 4.86 g (93%) of N- (2-fluoro-5-nitrophenyl) benzamide. ¹ H NMR (300 MHz,

311

CDC1 ₃₎ δ 9.48 (dd, 1 H, J = 6, 8 Hz, J = 2.81 Hz), 8.17 (br s, 1H), 8.03 (m, 1H), 7.92 ( m, 2H), 7.52-7.65 (m, 3H), 7.31 (d, 1H, J = 9.2 Hz).

(Ii)

A mixture of 4.86 g (18.7 mmol) of N- (2-fluoro-5-nitrophenyl) benzamide and 486 mg of 10% Pd / C in 80 mL of 1: 1 THF and MeOH was saturated with hydrogen at 23 ° C. After 2.5 hours, the reaction mixture was filtered through celite and concentrated to give 3.92 g (91%) of N- (5-amino-2-fluorophenyl) benzamide. MS (ESI +) [M + H] / z calcd 231, found 231.

(Iii)

6- [N- (3-benzamido-4-fluorophenyl) amino] -1- (2-trimethylsilanylethoxymethyl-3-E-styryl-1H-indazole) was prepared in a similar manner to Example 48 (a), step (iii) except that N- (5-amino-2-fluorophenyl) benzamide and the compound prepared in Example 14, step (i) were used as starting materials. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.38 ( dd, 1H, J = 6.84Hz, J =

2.73 Hz), 8.09 (d, 1H, J = 3.08 Hz), 7.86-7.91 (m, 3H), 7.48-

7.61 (m, 5H), 7.28-7.45 (m, 4H), 7.19 (d, 1H, J = 1.7 Hz), 7.08 (dd, 1H, J = 10, 48 Hz), 6.90-6.96 (m, 2H), 6.03 (bs, 1H), 5.66 (s, 2H), 3.62 (t, 2H, J = 8.14 Hz) 0.91 (t, 2H, J =

8.32 Hz), 0.0 (s, 9H). MS (ESI +) [M + H] / z calcd 579,

312 measured 579. Anal. Calcd: C, 70, 56. H, 6.10, N, 9.68.

Found: C, 20.26. H, 6.08. N, 9.16.

Example 48 (a)

6- [N- (5 - ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) -2-fluoro-4-methylphenyl) amino] -3-E- [2- (pyridine-2- yl) ethenyl] -lH-indazole

Example 48 (a) was prepared in a similar manner to Example 41 (a) from the starting material described below. ¹ H NMR (300 MHz, CD ₃ OD) δ 8.54 (d, 1H, J = 4.8 Hz),

7.95 (d, 1H, J = 9.49Hz), 7.84 (td, 1H, J = 7.71Hz, J = 1.78)

Hz), 7.70 (d, 1H, J = 7.95 Hz), 7.53 (d, 1H, J = 16.59Hz),

7.40 (d, 1H, J = 7.92 Hz), 7.29 (qd, 1H, J = 7.45 Hz, J = 1.07

Hz), 7.11 (d, 1H, J = 11.8), 7.03-7.06 (m, 2H), 6.71 (s, 1H),

4.50 (QR 2H, J = 7.16 Hz), 2.27 (s, 3H), 2.26 (s, 3H), 1.38 (T, 3H, J = 7.11 Hz). MS (ESI +) [M + H] / z calculated 496, measured 496th Anal, Calculation: C, 67, 86, H, 5.29. N, 19.79. measured : C, H, 5.50; N, 18.61

The starting material was prepared as follows:

(I)

A mixture of 1.0 g (5 mmol) of 1-fluoro-5-methyl-2,4-dinitrobenzene and 200 mg of 10% Pd / C in 20 mL of MeOH was saturated with hydrogen at 23 ° C for 24 hours. The reaction mixture was filtered through celite and

313 concentrated. Purification by silica gel chromatography (ethyl acetate / hexane 1: 1) gave 613 mg (87%) of 4-fluoro-6-methylbenzene-1,3-diamine.

(Ii)

To a solution of 566 mg (2 mmol) of 2-trimethylsilanylethyl carbonate 4-nitrophenyl ester in 4 mL of DMF at 23 ° C under argon was added 12 mg (0.1 mmol) of DMAP, 0.35 mL (2 mmol) of DIEA and 4-fluoro-6-methylbenzene-1,3-diamine. The resulting solution was heated at 50 ° C for 48 hours. The reaction mixture was quenched with saturated aqueous NaHCO 3, and extracted with 3 x 20 mL EtOAc. The EtOAc was removed in vacuo and the residue was redissolved in Et ₂ O, then washed with 3N aqueous NaOH, water, brine, dried over Na ₂ SO ₄ , filtered and concentrated. Purification by silica gel chromatography (ethyl acetate / hexane 2: 8 to 7: 3) gave 160 mg (28%) of (5-amino-4-fluoro-2-methyl-phenyl) -carbamic acid 2-trimethylsilanylethyl ester. MS (ESI +) [M + H] / z calcd 634, found 634.

(Iii)

To a mixture of 224 mg (0.47 mmol) of 6-iodo-3 - ((E) -2-pyridin-2-ylvinyl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazole, 160 mg (0.56 mmol) of 2- 5-Amino-4-fluoro-2-methyl-phenyl) -carbamic acid trimethylsilanylethyl ester, 214 mg (0.66 mmol) of Cs ₂ CO 3, 5.4

314 mg, (0.0059 mmol) of PdCl 2 (PPh ₃ ) ₂ and 10 mg (0.0176 mmol) of BINAP under argon at 23 ° C were added 0.5 mL of toluene. The resulting mixture was heated to 80 ° C for 16 hours. The reaction mixture was cooled to 23 ° C, and then diluted with 20 mL of water and extracted with 3 x 50 mL of EtOAc. The organic layers were washed with 30 mL of water, 30 mL of brine, dried over Na ₂ SO ₄ , filtered and concentrated to a foam. Silica gel column chromatography (ethyl acetate / hexane 3: 7) gave 98 mg (33%) of {4-fluoro-2-methyl-5- [3 - ((E) 2-pyridin-2-ylvinyl)] 2-trimethylsilanylethyl ester -1- (2-trimethylsilanylethoxymethyl) -1H-indazol-6-ylamino] phenyl} carbamic acid. TLC (7: 3 hexane)

and ethyl acetate) Rf sm 0.42, R _f p 0.23. ¹ H NMR (CDCl 3) δ 8.64 (Dd, 1H, J = 4.79Hz, J = 0, 86 Hz), 7.94 (d, 1H, J = 8.71 Hz), 7, 91 (bs, 1H), 7.86 (D, 1H, J = 16 , 41 Hz) 7.69 (td, 1 H, J = 7.72

Hz, J = 1.8 Hz), 7.55 (d, 1 H, J = 16.44 Hz), 7.49 (d, 1 H, J =

7.91 Hz), 7.17 (qd, 1H, J = 7.44 Hz, J = 0.98 Hz), 6.99 (dd,

1H, J = 8.67Hz, J = 1.89 Hz), 6.93 (d, 1H, J = 11.2 Hz), 6.25 (bs, 1H), 5.95 (d, 1H, J = 1.97 Hz), 5.70 (s, 2H), 4.25 (T, 2H, J = 8.53Hz; 3.60 (t, 2H, J = 8.24 Hz), 2.22 (with, 3H), 1.04 (t, 2 H, J = 8.54 Hz), 0.9 (t, 2H, J = 8.25) Hz), 0.05 (with,

9H), 0.0 (s, 9H). ¹³ C NMR (CDCl ₃ , 75 MHz) δ 156.0, 154.4, 149.8,

142.9, 142, 8, 142.5, 136, 6, 132, 1, 130, 1, 130, 5, 128.7, 128, 5,

124.3, 122.2, 122.0, 121.8, 118.2, 117.3, 117.0, 115.1, 95.2,

77, 6, 77, 4, 66.5, 63.7, 17, 9, 17.2, -1.3. FTIR cm ^-1 : 3326

2947, 1716, 1617, 1534, 1514, 1244, 1057. MS (ESI +) [M + H] / z calcd 634, found 634.

(Iv)

.315

The above aniline was prepared in a similar manner to Example 11. NMR (300 MHz, CD ₃ OD) δ 8.54 (m, 1H), 7.91 (dd, 1H, J = 8.74 Hz, J = 0) 58 Hz), 7.83 (td, 1H, J = 7.72 Hz, J = 1.79 Hz), 7.80 (d, 1H, J = 16.52 Hz), 7.69 (d, 1 H, J =

7.98 Hz), 7.52 (d, 1H, J = 16.58 Hz), 7.29 (qd, 1H, J = 7.43)

Hz, J = 1.07 Hz), 6.94-6.99 (m, 2H), 6.83 (d, 1H, J = 11.98

Hz), 6.82 (d, 1H, J = 7.49 Hz), 2.15 (s, 3H). MS (ESI +) [M + H] / z calcd 360, measured 360.

Example 48 (b)

6- [N- (5 - ((1,3-dimethyl-lH-pyrazol-5-yl) carboxamido) -2-fluoro-4-methylphenyl) amino] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

Example 48 (b) was prepared in a similar manner to Example 48 (a) except that 2,5-dimethyl-2H-pyrazole-3-carboxylic acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3- carboxylic acid. ¹ H NMR (300 MHz,

DMSO · -d ₆ ) δ 12 8 (s, 2H) , 9.71 (S, 1 H), 8.59 (m, IH), 8.11 (with, 1H), 8.00 (D, 1 H, J = 8.75 Hz), 7.87 (d, 1H, J = 16.37) Hz), 7, 80 (Td, 1H, J = 7.66 Hz, J = = 1.81 Hz) 7.74 (d, 1H, J = 7, 88 Hz), 7.49 (D, 1 H, J = 16, 38 Hz), 7.34 (d, 1H, J = 8.16) Hz), 7.26 (M, LH) 7.21 (d, 1H, J = 12.14 Hz), 6.97 (dd, IH, J = 8.76 Hz), 6.88 (s, 1 H) , 6.79 (5, 1H), 3.98 (s, 3H), 2.20 (with, 3H), 2.19 (with, 3H). MS (ESI +) [M + H] / z calc'd 482, measured 482nd Anal. calculation: C, 67.35. H, 5.02, N, 20.36. measured : C,

H, 5.25; N, 19.68.

Example 49 (a)

316

6- [N- (3 - ((1,3-dimethyl-1H-pyrazol-5-yl) carboxamido) -4-fluorophenyl) amino] -3-E- [2- (pyridin-2-yl) ethenyl] -1H indazol

The compound of Example 49 (a) was prepared in a similar manner to Example 48 (a) dimethyl-2H-pyrazole-3-carboxylic acid except for the following: 2,5acid was used in place of 2-ethyl-5-methyl-2H-pyrazole-3 -carboxylic acid, in step (ii), (5-amino-2-fluoro-phenyl) -carbamic acid 2-trimethylsilanylethyl ester, prepared as described below, was used in place of (5-amino-4-fluoro-2-methyl-phenyl) -carbamic acid 2-trimethylsilanylethyl ester, solvent was DME and biphenyl-2-

yldicyklohexylfosfán. ^T H NMR (300 MHz, CD ₃ OD) δ 12.7 (s, 1H), 9.94 (s, 1H); 8.48 (m, 1H), 8.40 (s, 1 H), 8.02 (d, 1 H, J = 6.77 Hz), 7.87 (d, 1H, J = 16.37 Hz), 7.80 (d, 1 H, J = 7, 63 Hz, J = 1.81 Hz), 7.64 (d, 1 H, J = = 7.88 Hz), 7.49 (d, 1 H, J =

16.39 Hz), 7.42 (dd, 1H, J = 6.65 Hz, J = 2.68 Hz), 7.24 (m,

2H), 7.06 (m, 2H), 6.96 (dd, 1H, J = 8.81 Hz, J = 1.82 Hz),

6.85 (s, 1H); 4.0 (s, 3H); 2.20 (s, 3H). MS (ESI +) [M + H] / z calcd 468, found 468. Anal, calcd: C, 66.80, H,

4.74, N, 20.97. Found: C, 66.01, H, 4.72, N, 20.81.

(I)

317

To a solution of 9.82 g (54 mmol) of 1-fluoro-2-isocyanato-4-nitrobenzene in 40 mL of THF at 23 ° C under argon was added 7.72 mL (54 mmol) of 2-trimethylsilanylethanol. The resulting mixture was stirred for 11 hours, and then heated to 50 ° C for 2 hours. The reaction mixture was allowed to cool to 23 ° C, quenched with saturated aqueous NaHCO 3 and extracted with 3x100 mL EtOAc. The combined ethyl acetate layers were washed with 2 x 90 mL 1 N aqueous HCl, 90 mL water and 90 mL brine, dried over Na ₂ SO ₄ , filtered and concentrated to a yellow solid. Silica gel chromatography (ethyl acetate / hexane 2: 8) gave 12.3 g (77%) of (2-fluoro-5-nitrophenyl) -carbamic acid 2-trimethylsilanylethyl ester. ¹ H NMR (300 MHz, CDCl 3) δ 9.06 (dd, 1H, J = 6.89 Hz, J = 2.63 Hz), 7.89 (m, 1H), 7.20 (m, 1H) 6.91 (bs, 1H), 4.31 (t, 2H, J = 8.67 Hz), 1.06 (t, 2H, J = 8.67 Hz), 0.05 (s, 9H ). LCMS (ESI-) [M + H] / z calc 299, found 299.

(Ii)

NH,

A mixture of (2-fluoro-5-nitrophenyl) carbamic acid 2-trimethylsilanylethyl ester (3.00 g, 10 mmol) and 300 mg of 10% Pd / C in 30 mL of methanol was saturated with hydrogen at 23 ° C. The resulting mixture was stirred for 24 hours. The reaction mixture was filtered through celite and concentrated to give 2.62 g (97%) of (5-amino-2-fluorophenyl) -carbamic acid 2-trimethylsilanylethyl ester. ¹ H NMR (300 MHz, CDCl ₃ ) δ 7.52 (m, 1H), 6.85 (dd, 1H, J = 10.8,

Hz, 1 = 8.69 Hz), 6.73 (bs, 1H), 6.28 (m, 1H), 4.27 (t, 2H, J = 8.57 Hz), 3.0-4 4 (bs, 2H), 1.06 (t, 2H, J = 8.58 Hz), 0.07 (s, 9H).

318

Example 49 (b)

6- [N- (3 - ((1,3-dimethyl-lH-pyrazol-5-yl) carboxamido) -4-methyl-phenyl) amino] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

CC -VR and WHAT- Example compound 49 (b) she was ready like as in the example 49 (a) except for that 1-methyl-2- isocyanato-4-nitrobenzene was used instead of l-fluoro-2-

of isocyanato-4-nitrobenzene in step (i). ¹ H NMR (300 MHz, CDCl 3)

δ 8.59 (m, 1H), 8.35 (s, 1H), 8.00 (D, 1H, J = 8.73Hz), 7.87 (D, 1H, J = 16.38 Hz), 7.80 (td, 1H, J = 7.66 Hz, J = 1 85 Hz), 7.64 (d, 1 H, J = 7.85 Hz), 7 , 49 (d, 1 H, J = 16, 35 Hz ) 7.26 (m, 1H), 7.19 (M, 2H), 7.09 (D, 1H, J = 1.48 HZ), 7 02

(dd, 1H, J = 8.17 Hz, J = 2.24 Hz), 6.97 (dd, 1H, J = 8.79 Hz, J = 1.80 Hz), 6.81 (bs, 1H), 4.00 (s, 3H), 2.20 (s, 3H), 2.18 (s, 3H). LCMS (ESI +) [M + H] / z calcd 464, found 464.

Example 49 (c)

6- [N- (3-acetamido-4-fluorophenyl) amino] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

The compound of Example 49 (c) was prepared in a similar manner to Example 49 (a) except that acetic anhydride was used instead of 2,5-dimethyl-2H-pyrazole-3-carboxylic ^{acid; H} NMR (300 MHz, CD 3 OD) δ 8.44 (m, 1H); 7.82 (d, 1H);

319

7.70 (m, 3H), 7.55 (d, 1H), 7.41 (d, 1H, J = 16.4 Hz), 7.19 (m, 1H), 7.03 (s, 1H) ), 6.94 (m, 1H), 6.87 (m, 2H), 2.11 (s, 3H). LCMS (100% area) R t = 4.53 min (pos) [M + H] / z calcd 388.4, measured 388.4.

Examples 49 (d) -49 (x) can be prepared in a similar manner to that described in Example 49 (a).

Example 49 (d)

Example 49 (e)

Example 49 (f)

320

Example 49 (g)

Example 49 (h)

Example 49 (i)

Example 49 (j)

321

Example 49 (k)

Example 49 (1)

Example 49 (m)

Example 49 (n)

Example 49 (o)

322

Example 49 (p)

Example 49 (q)

Example 49 (r)

Example 49 (s)

323

Example 49 (t)

Example 49 (u)

Example 49 (v)

Example 49 (w)

324

Example 49 (x)

Example 50

6- [3- (5-amino-2-fluorophenyl) carbamoyl-5-methyl-2-ethyl-2H-pyrazol-4-yl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H- indazole

Example 50 was prepared from the starting material described below in a similar manner to that described in Example 11. MS (ESI +) [M + H] / z calcd 482, measured 482. Calcd: C, 67.35, H, 5, O, N, 20.36. Found: C, 66.70, H, 5.09, N, 19.95.

(I)

325

2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (2-fluoro-5-nitrophenyl) amide was prepared in a manner analogous to Example 47, Step (i) except that 2-ethyl-5-methyl -2Hpyrazole-3-carboxylic acid and HATU were used in place of benzoyl chloride. MS (ESI +) [M + H] / z calcd 293, found 293.

(Ii)

2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid (2-fluoro-5-nitrophenyl) -amide was prepared in a similar manner to Example 40 (b), step (i). MS (ESI +) [M + H] / z calcd 263, found 263.

(Iii)

6- [3- (5-amino-2-fluorophenyl) carbamoyl-5-methyl-2-ethyl-2H-pyrazol-4-yl] -3-E- [2- (pyridin-2-yl) ethenyl) -1 (2-trimethyl326 silanylethoxymethyl) -1H-indazole was prepared in a similar manner to Example 48 (a), step (iii) except that 2-ethyl-5-methyl-2H-2-ethyl-5-methyl-amide (5-amino-2-fluorophenyl) amide was prepared. pyrazole-3-carboxylic acid was used as starting material. MS (ESI +) [M + H] / z calcd 612, found 612.

Example 51

6-pyridin-4-yl-3-E- (N- (pyrrol-l-yl) imino-methyl) -lH-indazole

6-pyrid-4-yl-3-E- (N- (pyrrol-1-yl) iminomethyl) -1- (2-trimethylsilanylethoxymethyl-1H-indazole was converted to 6-pyrid4-yl-3-E- (N - (pyrrol-1-yl) iminomethyl) -1H-indazole in a manner similar to that described in Example 29 (3) / 11 NMR (300 MHz, CDCl 3) δ 8.76 (s, 1H), 8.67 (d (2H, J = 6.1 Hz), 8.53 (d, 1H, J = 8.4 Hz), 7.74 (s, 1H), 7.61 (d, 2H, J = 6.2 Hz) ), 7.54 (d,

1H, J = 8.5 Hz), 7.27-7.25 (m, 2H), 6.31-6.29 (m, 2H). MS (ES) [M + H] / z calcd 288, found 288. Anal. Calc'd: C (71.07), H (456), N (24.37). Found: C (70.81), H (4.57), N (24.14).

The starting material was prepared as follows:

A solution of 208 mg (0.59 mmol) of 6-pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde, 145 mg (1.76)

327 mmol) of N-aminopyrrole and 5.8 μΐ of acetic acid in 1 ml of ethanol were held at 95 ° C for 16 hours. The solution was then evaporated under reduced pressure and purified by silica gel chromatography to give 140 mg (57%) of 6-pyrid-4-yl-3-E (N- (pyrrol-1-yl) iminomethyl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazole as an oil. ^X H NMR (300 MHz, CDC1 ₃₎ δ 9.08 (s, IH);

8.71 (d, 2H, J = 6.1 Hz), 8.46 (d, 1H, J = 8.5 Hz), 8.34 (s, 1H), 7.85 (d, 2H, J) = 6.2 Hz), 7.80 (d, 1H, J = 8.5 Hz), 7.56 (t, 2H, J = 2.3 Hz), 6.25 (t, 2H, J = 2) 3 Hz), 5.93 (s, 1H),

5.74 (s, 2H), 3.64 (t, 2H, J = 7.9 Hz), 0.86 (t, 2H, J = 7.9

Hz), 0.00 (s, 9H).

Example 52 (a)

6- (7-aza-indazole-4-yl) -3-E-styryl-lH-indazole

The SEM compound of Example 52 (a) was converted to the compound of Example 52 (a) in a manner similar to that described in Example 27 (a). ^X H NMR (300 MHz, DMSO-de) δ 8 63 (d, IH, J = 4.8 Hz), 8.41 (d, IH, J = 85 Hz), 8.37 (s, IH) 7.99 (s, 1H), 7.76 (d, 2H, J = 7.3 Hz), 7.70 (d, 1H, J = 8.5 Hz), 7, 60-7, 85 ( m, 6H). HRMS (FAB) [M + H] / z calcd 338.1400, found 338.1389. Analyzed with 1.1 trifluoroacetic acid, calculated: C (60.21), H (3.51), N (15.13). Found: C (59.93), H (3.59), N (14.86).

The starting material was prepared as follows:

(I)

328

A solution of 1.0 g (1.90 mmol) of 3-styryl-1- (2-trimethylsilanylethoxymethyl) -6-trimethylstannyl-1H-indazole, 0.56 g (1.90 mmol)

1- (4-iodopyrazolo [3,4-b] pyridin-1-yl) ethanone, 116 mg (0.38 mmol) of AsPh ₃ and 87 mg (0.09 mmol) of Pd ₂ dba ₃ in 10 mL of degassed dioxane were heated in 110 ° C for 3 hours. The solution was then diluted with 50 mL of ethyl acetate, washed 2 over MgSO 4 and concentrated to dry on silica gel.

Purification by chromatography (46%) of the compound of Example x 10 mL brine, under reduced pressure.

gave 412 mg of solid. ¹ H

NMR (300 MHz CDC1 ₃ ) δ 8.82 (d, 1H, J = 5.8 Hz), 8.52 (s, 1H), 8.29 (D, 1H, J = 8.2 Hz), 8.05 (s, 1H); 7.73-7.32 (m, 10H), 5.86 (with, 2H); 3.69 (t, 2H, J = 8.2 Hz), 0.97 (t, 2H, J) = 8.2 Hz), -about, 03 (s, 9H).

(Ii)

A solution of 2.90 g (6.10 mmol) of 6-iodo-3-styryl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole, 2.00 g (6.12 mmol) of hexamethyldicin and 282 mg (0.24 mmol) of Pd (PPh ₃ ) ₄ in 10 ml degassed dioxane was heated at 110 ° C for 3 hours. The solution was then diluted with 200 mL ethyl acetate, washed with 2 x 20 mL brine, dried over MgSO 4 and evaporated under reduced pressure. Purification by silica gel chromatography gave 3 g (96%) of 3-styryl-1329 (2-trimethylsilanylethoxymethyl) -6-trimethylstannyl-1H-indazole as a yellow oil. ^X H NMR (300 MHz, CDC1 ₃₎ δ 8.02 (d, 1 H, J =

7.4 Hz), 7.71 (s, 1H), 7.71-7.29 (m, 8H), 5.77 (s, 2H), 3.65 (t, 2H, J = 16.3) Hz), 0.95 (t, 2H, J = 16.4 Hz), 0.38 (s, 9H), -0.03 (s, 9H).

(Iii) ABOUT mixture 820 mg (5.30 mmol) 4-chloro-lH-pyrazolo [3,4- bjpyridínu. 2.4 mg (16.0 mmol) of sodium iodide and 0.8 ml acetyl chloride v 6 ml of acetonitrile was heated to boil under

reflux condenser for 8 hours. The mixture was then treated with 10 mL of a 10% aqueous NaCC solution> 3 and 10 mL of a 10% aqueous NaHSC solution> 3 and held for 10 minutes. The mixture was extracted with 50 mL of ethyl acetate and the organic layers were washed with 10 mL of brine, dried over MgSO ₄ and evaporated under reduced pressure. Purification by silica gel chromatography gave 650 mg (42%) of 1- (4-iodopyrazolo [3,4-b] pyridin-1-yl) ethanone as a brown solid. ¹ H NMR (300 MHz, CDCl ₃ ) δ 8.39 (d, 1H, J = 5.0 Hz), 8.04 (s, 1H),

7.76 (d, 1H, J = 5.0 Hz); 2.88 (s, 3H).

(Iv)

330

1.2 g (8.8 mmol) of 1,7-dihydropyrazolo [3,4-b] pyridin-4-one, (Dorn, H. et al., Prakt. Chem., 324, 557-62, 1982) in 15 ml

POCl 3 at 0 ° C was treated with 2.5 mg (0.01 mmol) of PCl 5. The solution was allowed to warm to room temperature for 1 hour, then heated to 90 ° C and held for 3 hours. The solution was concentrated under reduced pressure, then treated with 50 mL of ice and water. The resulting mixture was extracted with 100 mL ethyl acetate and the organic layer was washed with 30 mL saturated aqueous sodium bicarbonate. The organic layer was dried over MgSO ₄ , then evaporated under reduced pressure to give 820 mg (60%) of 4-chloro-1H-pyrazolo [3,4-b] pyridine as a yellow solid. NMR (300 MHz, CDCl 3) δ 8.57 (d, 1H, J = 5.2 Hz), 8.25 (s, 1H), 7.28 (d, 1H, J = 5.2 Hz).

Example 52 (b)

6- (7-azaindol-4-yl) -3-E-styryl-lH-indazole

SEM-iodoindazole was converted to the compound of Example 52 (b) in a similar manner to that described in Example 27 (a). ^X H NMR (300 MHz, MeOH-d δ 8.40 (d, 1 H, J = 5.3 Hz), 8.53 (d, 1 H, J = 6 Hz), 7.74 to 7.35 (m (10H), 6.90 (s, 1H), HRMS (FAB) [M + H] / z calcd 337.1448, measured 337.1457 Analyzed with 0.3 H ₂ O, calcd: C (77.31 H, 4.90, N (16.39) Found: C (77.51), H (4.88), N (16.27).

The starting material was prepared as follows:

(I)

331

FROM

4-chloro-lH-pyrrolo [2,3-b] pyridine

Chem. Soc. PI, 2270-74, 1974) pyrrolo [2,3-b] pyridine similar to Example 52 (a). ^@ 1 H NMR (300 ^MHz, CDCl3) .delta

7.89 (d, 1H, J = 5.0 Hz), 7.58 Hz), 6.26 (bs, 1H).

(Clark, BA et al., J. was converted to 4-iodo-1H by the method described for MHz, MeOH-dJ δ 8.10 (m, 1H), (m, 1H), 7.50 (d, 1H) J = 5.0

Example 53 (a)

3- (lH-benzimidazol-2-yl) -N- (4-hydroxyphenyl) -lH-indazole-6-carboxamide

To a solution of 208 mg (0.7 mmol) of indazole-6-carboxylic acid formamide was added 82 mg

3- (1H-benzimidazol-2-yl) -1H (0.7 mL of dry dimethyl-4-aminophenol, mmol) followed by 312 mg (0.8 mmol) of HATU, and then 20 drops of triethylamine were added. The reaction was stirred through rooms. LC / MS showed the desired product component. The solvent was removed in vacuo. Remaining night

At as temperature the major residue was taken up in water and ethyl acetate. The layers were separated and the organic layer was concentrated in dissolved in 10 mL of methanol and half vacuum. The residue of this solution was purified by HPLC using a gradient

55% acetonitrile / water for 60 minutes

5% acetonitrile / water up to

0.1% trifluoroacetic acid in water. The title compound was isolated

332 as a 20 mg solid. ^X H NMR (methanol-d ₄₎ δ 6.87 (2H, d, 8.8 Hz), 7.55 (2H, d, 8.7 Hz), 7.61 (2H, m), 7.87 (2H, br s), 8.00 (1H, d, 8.4 Hz), 8.35 (1H, s), 8.52 (1H, d, 8.6 Hz). MS (APCI pos) 370.1.

The starting material was prepared as follows:

(I)

To 2.0 g (12.42 mmol) of lH-indole-6-carboxylic acid in 100 ml of water was added 8.56 g (124.2 mmol) of NaNO _second To this suspension was then slowly added dropwise a 16 mL 6N HCl addition funnel. The resulting suspension was left with stirring at room temperature overnight. The solid precipitate was filtered and washed with 50 mL of water to give 2.35 g (100%) of 3-formyl-1H-indazole-6-carboxylic acid. ¹ H NMR (DMSO-d 6) δ 14.46 (1H, s), 10.21 (1H, s), 8.26 (1H, s), 8.20 (1H, d, J =

8.5 Hz), 7.90 (1H, d, J = 8.3 Hz). MS (APCI positive) 205 (methyl ester).

(Ii)

To 2.35 g (12.42 mmol) of 3-formyl-1H-indazole-6-carboxylic acid in 60 mL of DMF was added 1.34 g (12.42 mmol) of 1,2-phenylenediamine and 13.66 mmol (1 , 1 eq) of sulfur powder. The mixture was then heated to reflux for 2 hours

333 for 6 hours. The reaction was monitored by TLC and LC-MS. After cooling, 50 mL of water was added to the reaction and the brown precipitate that formed was filtered and collected to give 3.1 g (90%) of 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid. acid. ^T H NMR (DMSO-d ₆₎ δ 14.01 (1H, s), 8.58 (1H, d, J =

8.5 Hz), 8.24 (1H, s), 7.87 (1H, d, J = 8.7 Hz), 7.64 (2H, m), 7.25 (2H, m). MS (APCI positive) 279.

Example 53 (b)

3- (lH-benzimidazol-2-yl) -N-cyclopropyl-lH-indazole-6-carboxamide

To 200 mg (0.719 mmol) of 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid in 30 mL of DMF was added 98 mg (0.719 mmol) of cyclopropylamine, 273 mg (0.719 mmol) of HATU and 0.1 ml (0.726 mmol) of triethylamine. This solution was allowed to stir at room temperature overnight. The reaction was worked up by washing with water and extracting with 3 x 50 mL ethyl acetate. The organic layer was then dried over MgSO 4, filtered and concentrated to give a dark oil. Flash column chromatography (30-70% ethyl acetate / petroleum ether) gave 0.130 g (57%) of 3- (1H-benzimidazol-2-yl) -N-cyclopropyl-1H-indazole-6-carboxamide as a yellow solid. NMR (DMSO-d ₆ ) δ 13.88 (1H, s), 8.63 (1H, m), 8.51 (1H, d, J = 8.5 Hz), 8.09 (1H, s) 7.75 (1 H, d, J =

8.7 Hz), 7.63 (2H, br s), 7.21 (2H, m), 2.89 (1H, m), 0.72 (2H, m), 0.63 (2H, m) ). MS (APCI positive) 318.1.

334

Example 53 (c)

3- (lH-benzimidazol-2-yl) -N- (4-hydroxy-3-methyl-phenyl) -lH-indazole-6-carboxamide

Example 53 (c) was prepared in a similar manner to that described in Example 53 (a) except that 3-methyl-4-aminophenol was used instead of 4-aminophenol. ¹ H

NMR, (DMSO-d 6) δ 8.59 (1 H, d, J = 8.3 Hz), 8.25 (1 H, s), 7.89 (1 H, dd, J = 1.3, 8.5 Hz), 7.68 (2H, br s), 7.28 (2H, m), 7.14 (1 H, d, J = 8.5 Hz) 6, 74 (1H, s), 6.68 (2H, dd, J = 3.0, 8.3

Hz). MS (APCI positive) 384.1.

Example 53 (d)

3- (1H-benzimidazol-2-yl) -N- (4-hydroxy-2,3-dimethylphenyl) -1H-indazole-6-carboxamide

The compound of Example 53 (d) was prepared in a similar manner to that described in Example 53 (a) except that

2,3-Dimethyl-4-aminophenol was used instead of 4-aminophenol. ¹ H

NMR (DMSO-de) 8 9.93 (1H, p }, 9, 22 (1 H, with) 9 8.56 (1 H, d, J = 5.5 Hz), 8.25 (1H, s) , 7.90 (1 H, d. J = θ, 5 Hz), 7.73 (1 H, br with) , 7.53 (1 H, br s), 7,23 (2H, br with) , 6r 92 (1 H, d, J = 8.3

335

Hz), 6.68 (1H, d, J = 8.5 Hz), 2.09 (6H, br s). MS (APCI positive) 398.4.

Example 53 (e)

3- (lH-benzimidazol-2-yl) -lH-indazole-6-carboxamide

The compound of Example 53 (e) was prepared in a similar manner to that described in Example 53 (a) except that

1,1,1,3,3,3-hexamethyldisilazane was used instead of 4-amino-

phenol. ^{Χ Η} NMR (DMSO-de) δ 13.91 (1 H, with) , 13, 04 (1 H, s), 8.52 (1H, d, J = 8.3Hz), 8.20 (1H, br s), 8.15 (1 H, s), 7.81 (1 H, d, J = 7.7 Hz), 7.75 (1H, d, J = 6.6) Hz), 7.51 (2H, m) 7.21 (2H, m). MS (APCI positive) 278.1.

Example 53 (f)

3- (lH-benzimidazol-2-yl) -N-benzyloxy-lH-indazole-6-carboxamide

The compound of Example 53 (f) was prepared in a similar manner to that described in Example 53 (a) except that O-benzylhydroxylamine was used instead of 4-aminophenol. ¹ H NMR (DMSO-d 6) δ 13.94 (1H, s), 13.06 (1H, s), 11.97 (1H, s), 8.55 (1H, d, J = 8.8 Hz) ), 8.02 (1H, s), 7.78 (1H, d, J = 8.3 Hz),

336

7.52 (1H, d, J = 8.3 Hz), 7.50 (3H, m), 7.40 (3H, m), 7.22 (2H, m), 4.97 (2H, s) ). MS (APCI positive) 384.2.

Example 53 (g)

3- (lH-benzimidazol-2-yl) -N- (3-fluoro-4-hydroxyphenyl) -lH-indazole-6-carboxamide

The compound of Example 53 (g) was prepared in a similar manner to that described in Example 53 (a) except that 3-fluoro-4-aminophenol was used instead of 4-aminophenol. ¹ H NMR (CH ₃ OD) δ 8.58 (1H, d, J = 8.5 Hz), 8.20 (1H, s), 7.84 (1H, d, J = 8.7 Hz), 7.68 (2H, br s), 7.63 (1H, dd, J = 2.4, 13 Hz),

7.29 (3H, m), 6.92 (1H, t, J = 9.2 Hz). MS (APCI positive)

388.3.

Example 54 (a)

3- (5,6-Difluoro-1H-benzimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-6-carboxamide

Using the same procedure as for the synthesis of 3- (1H-benzimidazol-2-yl) -1H-indazole-6-carboxylic acid in Example 53 (a), step (ii), N- (4-hydroxyphenyl) -3-formyl-1H-337 indazole-6-carboxamide and 4,5-difluoro-1,2-phenylenediamine afforded 3- (5,6-difluoro-1H-benzimidazol-2-yl) -N- (4-hydroxyphenyl) -1Hindazole-6-carboxamide as a tan solid, ¹ H NMR (DMSO-d ₆ ) δ 13.99 (1H, s), 13.27 (1H, s), 10.21 (1H, s), 9.25 (1H, s), 8.52 (1H, d, J = 8.7Hz), 8.21 (1H, s), 7.85 (1H, d, J = 9.0Hz), 7.80 (1H, t, J = 9.8 Hz), 7.55 (2H, d, J = 8.7 Hz), 7.47 (1H, t, J = 9.8 Hz), 6.75 (2H, d, J = 8 7 Hz). MS (APCI positive) 406.

The starting material was prepared as follows:

· OH

To a solution of 1.6 g (8.4 mmol) of 3-formyl-1H-indazole-6-carboxylic acid and 1.8 g (16.8 mmol) of 4-aminophenol in 35 ml of dry dimethylformamide was added 3.8 g (16, 8 mmol) of HATU followed by 1.4 mL (10.1 mmol) of triethylamine. The reaction was stirred at room temperature and monitored by TLC and LC / MS. After two hours the reaction was complete. The solvent was removed in vacuo and the product was purified by flash column chromatography using a 1: 1 mixture of ethyl acetate and petroleum ether to pure ethyl acetate. N- (4-hydroxyphenyl) -3-formyl-1H-indazole-6-carboxamide was isolated as a yellow-brown solid. ¹ H NMR (DMSO-d ₆ ) δ 6.79 (2H, d, 8.9 Hz), 7.59 (2H, d, 8.9 Hz), 7.94 (1H, d, 9.8 Hz) 8.24 (1H, d, 8.2 Hz), 8.31 (1H, s), 9.31 (2H, br s), 10.27 (2H, s). MS (APCI pos) 282.1.

Example 54 (b)

338

3- (5,6-Dichloro-1H-benzimidazol-2-yl) -N- (4-hydroxyphenyl) -1Hindazole-6-carboxamide OH

The compound of Example 54 (b) was prepared in a similar manner to that described in Example 54 (a) except that

4,5-Dichloro-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2-phenylenediamine. ^X H NMR (DMSO-de) δ 14.08 (IH, s), 13.38 (IH, s), 10.22 (IH, s), 9.27 (IH, s), 8.52 (H , d, J =

8.7 Hz), 8.23 (IH, s), 8.02 (IH, s), 7.86 (IH, d, J = 8.7 Hz), 7.70 (IH, s), 7 55 (2H, d, J = 8.7Hz), 6.75 (2H, d, J = 8.7Hz). MS (APCI positive) 438.

Example 54 (c)

3- (5-Methoxy-1H-benzimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-6-carboxamide OH

Example 54 (c) was prepared in a similar manner to that described in Example 54 (a) except that 4-methoxy-1,2-phenylenediamine was used instead of 4,5-difluoro-

1,2 phenylenediamine. ^X H NMR (DMSO-de) δ 13.76 (IH, s), 12.77 (IH, s), 10.13 (IH, s), 9.17 (IH, s), 8.45 (H , d, J = 8.3 Hz), 8.11 (1H, s), 7.75 (1H, d, J = 8.6 Hz), 7.46 (2H, d, J =

8.7 Hz), 7.32 (1H, d, J = 8.3 Hz), 6.91. (IH, s), 6.77 (IH,

339

m), 6.67 (2H, d, J = 8.7 Hz), 3.72 (3H, s). MS (APCI positive) 400.

Example 54 (d)

3- [1H-naphtho [2,3-d] imidazol-2-yl] -N- (4-hydroxyphenyl) -1H-indazole-6-carboxamide.

Example 54 (d) was prepared in a similar manner to that described in Example 54 (a) except that

2,3-Naphthalenediamine was used in place of 4,5-difluoro-1,2-phenylenediamine. NMR (DMSO-d ₆ ) δ 14.11 (1H, s), 13.10 (1H,

s), 10.24 (1H, s), 9.27 (1H, s), 8.64 (1H, d, J = 8.7 Hz),

8.28 (1H, s), 8.25 (1H, s), 7.97 (2H, m), 7.73 (1H, br s),

7.89 (1H, d, J = 8.6Hz), 7.56 (2H, d, J = 8.7Hz), 7.38 (2H,

b), 6.76 (2H, d, J = 8.7 Hz). MS (APCI positive) 420.

Example 54 (e)

3- [1H-naphtho [1,2-d] imidazol-2-yl] -N- (4-hydroxyphenyl) -1H-indazole-6-carboxamide.

340

Example 54 (e) was prepared in a similar manner to that described in Example 54 (a) except that

1,2-Naphthalenediamine was used instead of 4,5-difluoro-1,2-phenylenediamine. ¹ H NMR (DMSO-d 6) δ 13.93 (1H, s), 13.38 (1H,

S), 10.23 (1H, s), 9.27 (1H, s), 8.70 (2H, m), 8.22 (1H, s),

8.00 (1H, d, J = 8.0Hz), 7.87 (1H, m), 7.72 (3H, m), 7.57 (2H, d, J = 8.7Hz), 6.76 (2H, d, J = 8.6 Hz): MS (APCI positive) 420.

Example 54 (f)

3- (4,5-Dimethyl-1H-benzimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-6-carboxamide

OH

The compound of Example 54 (f) was prepared similar to that described in Example 54 (a) except that 3,4-dimethyl-1,2-. phenylenediamine was used instead of 4,5-difluoro-1,2-phenylenediamine. ^T H NMR (DMSO-de) δ 13.77 (1 H, d, tautomers),

12.70 (1H, d, tautomers), 10.11 (1H, s), 9.16 (1H, s), 8.48 (1H, d, J = 8.3 Hz), 8.09 (1H) , s), 7.73 (1H, d, J = 8.6Hz), 7.47 (2H, d, J = 8.7Hz), 7.10 (1H, d, J = 8.3Hz) 6.93 (1H, d, J = 8.3 Hz), 6.65 (2H, d, J = 8.7 Hz), 2.49 (3H, s), 2.24 (3H, s ). MS (APQ positive) 398.4.

Example 54 (g)

3- (5-tert-Butyl-1H-benzimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-6-carboxamide

341

Example 54 (g) was prepared in a similar manner to that described in Example 54 (a) except that 4-tert-butyl-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2-phenylenediamine. ^X H NMR (acetone-d) δ 12.88 (IH, s), 9.47 (IH, s), 8.63 (1H, d, J = 8.7 Hz), 8.18 (IH, s ), 7.82 (1H, d, J = 8.3Hz), 7.57 (4H, m), 7.26 (IH, d, J = 8.4Hz),

6.74 (1H, d, J = 8.3 Hz), 1.31 (9H, s). MS (APCI positive) 426.

Example 54 (h)

3- (5-trifluoromethyl-lH-benzoimidazol-2-yl) -N- (4-hydroxyphenyl) -lH-indazole-6-carboxamide

Example 54 (h) was prepared in a similar manner to that described in Example 54 (a) except that 4-trifluoromethyl-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2-phenylenediamine. ¹ H NMR (methanol-d ₄ ) δ 6.86 (2H, d,

8.9 Hz), 7.54 (2H, d, 8.9 Hz), 7.6 (1H, dd, 8.5 Hz), 7.83 (IH, d, 83 Hz), 7.89 ( 1H, dd, 8.6 Hz), 8.04 (1H, br s), 8.25 (1H, s), 8.61 (1H, d, 8.6 Hz). MS (APCI pos) 438.1.

342

Example 54 (i)

3- (5-fluoro-1H-benzimidazol-2-yl) -N- (4-hydroxyphenyl) -1H-indazole-6-carboxamide OH

Example 54 (i) was prepared in a similar manner to that described in Example 54 (a) except that 4-fluoro-1,2-phenylenediamine was used in place of 4,5-difluoro-

1,2-phenylenediamine. ¹ H NMR (acetone-de) δ 13.40 (1H, b), 12.47 (1H, b), 9.74 (1H, s), 8.67 (1H, d, J = 8.6 Hz) ), 8.66 (1H, s),

8.29 (1H, s), 7.94 (1H, d, J = 8.5Hz), 7.67 (2H, J = 8.4Hz),

7.64 (1H, m), 7.40 (1H, m), 7.05 (1H, t, J = 8.5 Hz), 6.83 (2H, d, J = 8.4 Hz). MS (APCI pos) 388.

Example 54 (j)

3- (5H- [1,3] dioxolo [4,5- f] benzimidazol-6-yl) -N- (4-hydroxyphenyl) -1H-indazole-6-carboxamide OH

The compound of Example 54 (j) was prepared in a similar manner to that described in Example 54 (a) except that

4,5-methylenedioxy-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2-phenylenediamine. ¹ H NMR (methanol-d ₄ ) δ 6.85 (2H, d,

343

8.9 Hz), 7.15 (2H, s), 7.54 (2H, d, 8.9 Hz), 7.86 (1H, dd, 8.6 Hz), 8.23 (1H, s) 8.55 (1H, dd, 8.5 Hz). MS (APCI pos) 414.1.

Example 54 (k)

3- (5,6-dimethoxy-lH-benzoimidazol-2-yl) -N- (4-hydroxyphenyl) -1Hindazol-6-carboxamide

The compound of Example 54 (k) was prepared in a similar manner to that described in Example 54 (a) except that

4,5-dimethoxy-1,2-phenylenediamine was used instead of 4,5-difluoro-1,2-phenylenediamine. ¹ H NMR (methanol-d ₄ ) δ 3.98 (6H, s),

6.85 (2H, d, 8.78 Hz), 7.29 (2H, br s), 7.54 (2H, d, 8.73 Hz),

7.86 (1H, d, 8.57Hz), 8.24 (1H, s), 8.57 (1H, d, 8.58Hz). MS (APCI pos) 430.1.

Example 54 (1)

3- (5-chloro-1H-benzimidazol-2-yl) -N- (4-hydroxyphenyl) -ΙΉ-indazole-6-carboxamide

The compound of Example 54 (1) was prepared in a similar manner to that described in Example 54 (a) except that

4-chloro-1,2-phenylenediamine was used instead of 4,5-difluoro-

1,2-phenylenediamine. ¹ H NMR (methanol-d ₄ ) δ 8.62 (1H, d, J = 8.6)

344

Hz), 8.30 (1H, s), 7.90 (1H, dd, J 1 = 8.6 Hz, J 2 = 1.3 Hz),

7.69 (b, 2H), 7.56 (2H, d, J = 6.89 Hz), 7.33 (1H, dd, J1 = 8.59, J2 = 1.97 Hz), 6.88 (2H, d, J = 6.89Hz). MS (APCI pos)

404.1.

Example 55

3-H-benzoimidazol-2-yl-6-pyridin-4-yl-lH-indazole

The SEM compound of Example 55 was converted to the compound of Example 55 in a similar manner to that described in Example 27 (a). ¹ H NMR (300 MHz, CDCl ₃ + MeOH-d ₄ + DMSO-d 6) δ 8.71-8.64 (m, 3H), 8.03 (s, 1H), 7.86 (dd, 2H, J = 4.7, 1.6 Hz), 7.77-7.72 (m, 3H), 7.32 (dd, 2H, J = 6.0, 3.1 Hz). HRMS (FAB) [M + H] / z calcd 312.1244, measured 312.1253. Analyzed with 1.40 H ₂ O, calculated: C (67, 80), H (4.73), N (20.81). Found: C (68.06), H (4.45), N (20.68).

The starting material was prepared as follows:

A solution of 0.70 g (2.0 mmol) of 6-pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-3-carbaldehyde, 0.26 g (2.4 mmol) of benzene-1,2 of diamine and 77 mg (2.4 mmol) of sulfur in 10 mL of DMF was heated in an oil bath at 90 ° C overnight. The resulting mixture was poured into 200 mL of brine, and then extracted 3 times

345 mL EtOAc. The combined organic layers were dried over MgSO ₄ and concentrated under reduced pressure. The resulting oil was purified by silica gel chromatography to give 0.75 g (65%) of 6-pyridin-4-yl-1- (2-trimethylsilanylethoxymethyl) -3- [1- (2-trimethylsilanylethoxymethyl) -1H-benzimidazol-2-yl] 1 H-indazole as a light brown oil. ¹ H NMR (CDCl ₃ ) δ 8.82 (d, 1H, J = 8.5 Hz), 8.73 (d, 1H, J = 5.8 Hz), 7.94-7.89 (m, 2H), 7.87 (s, 1H), 7.69-7.62 (m, 4H), 7.40-7.34 (m, 2H), 3.70-3.49 (m, 4H) 0.94 (t, 2H, J = 8.3Hz), 0.67 (t, 2H, J = 8.2Hz), -0.03 (s, 9H), -0.13 (s, 9H).

Example 56

6- [3- (propyn-3-ylcarbamoyl) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

A solution of 55.4 mg (0.15 mmol, synthesis described below) of 2- {1- [3 - ((E) -2-pyridin-2-ylvinyl) -1H-indazol-6-yl] methanoyl] benzoic acid, 15, 4 μΐ (0.225 mmol) of propargylamine and 41.8 μΐ (0.30 mmol) of triethylamine, dissolved in 1.5 ml of DMF, were treated with 62.7 mg (0.165 mmol) of O- (7-azabenzotriazol-1-yl) N, N, N ', N'tetrametyluróniumh.exafluórfosfátu. After stirring for one hour, the mixture was concentrated under high vacuum and purified by reverse phase preparative chromatography on a C18 column. The resulting 40 mg of product was further purified by ring-plate chromatography with 25% CH ₃ CN and CH ₂ Cl ₂ to give 16.5 mg of the product as a white solid (27% yield). ¹ H NMR

346 (DMSO-d 6) δ 13.30 (s, ΙΗ), 8.58 (d, J = 5.00 Hz, 1H), 8.05 (d, J = 8.29 Hz, 1H), 7, 92 (d, J = 16.2 Hz, 1 H), 7.79 (m, 3H),

7.63 (d, J = 8.25 Hz, 1H), 7.53 (m, 3H), 7.32 (s, 1H), 7.27 (m, 2H), 6.89 (d, J) = 8.48 Hz, 1H). Anal, calculation, for

C25H18N4O2 · 0.5 _H2O: C, 72.27, H, 4.61, N, 13.49. Measured: C,

H, 4.62; N, 13.69.

(I)

Synthesis of 2- {1- [3 - ((E) -2-pyridin-2-ylvinyl) -1H-indazol-6yl] methanoyl} benzoic acid. Solution 402 mg (0.805 mmol, synthesis described below) 2- {1- [3- ((E) -2-pyridin-2-ylvinyl) -1 (2-trimethylsilanylethoxymethyl) -1H-indazol-6-yl] methanoyl} benzoic acid, 215 μΐ (3.22 mmol) of ethylenediamine and 6.44 ml (6.44 mmol) of IM TBAF in THF were stirred at 90 ° C in an oil bath for 4 hours. The crude reaction mixture was quenched with 386 μΐ (6.44 mmol) acetic acid, diluted with 100 mL ethyl acetate, extracted with 2 x 20 mL IM sodium bicarbonate solution, 5 x 20 mL brine, dried over magnesium sulfate, filtered and concentrated to a volume of 3 mL. The resulting crude was purified by reverse phase preparative chromatography on a C18 column to give 211 mg of the title compound as a yellow solid (71% yield). ¹ H NMR (DMSO-d 6) δ 13.50 (bs, 1H), 8.68 (d, J = 5.27 Hz, 1H), 8.29 (d, J = 8.86 Hz, 1H) 8.13-7.90 (m, 4H); 7.81-7.43 (m, 7H).

(Ii)

347

Synthesis of 2- {1- [3 - ((E) -2-pyridin-2-ylvinyl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazol-6-yl] methanoyl} benzoic acid. A solution of 477 mg (1.0 mmol) of 6-iodoindazole, dissolved in 10 mL of THF, at -100 ° C was treated dropwise with 440 μΐ (1.10 mmol) of 2.5M n-butyllithium in hexane, stirred for 5 min. minutes at this temperature, and then treated with a solution of 222 mg (1.5 mmol) of phthalic anhydride in 1.0 mL of THF. The resulting mixture was allowed to warm slowly to room temperature, where it was devoid of THF, diluted with ethyl acetate, extracted with 1 N citric acid, extracted with brine, dried over magnesium sulfate and concentrated to an oil. The oil was triturated with methylene chloride and diethyl ether to give 484 mg (81% yield) of the title compound as a white solid. NMR (DMSO-d 6) δ 8.67 (d, J = 5.09 Hz, 1H), 8.31 (d, J = 8.85 Hz, 1H), 8.08-7.55 (m, 4H) 7.50-7.37 (m, 2H), 5.81 (s, 2H), 3.53 (t, J = 8.10 Hz, 2H), 0.78 (t, J = 8, 15 Hz, 2H), 0.12 (S, 9H).

Example 57

6- [3 - ((1,3-dimethyl-lH-pyrazol-5-yl) carboxamido) phenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -lH-indazole

348

The compound of example 57 was prepared in a similar manner to Example 58 ^{Χ Η} NMR (300 MHz, _DMSO-d6) δ 13.15 (s, 1H), 10.17 (s, 1H), 8.60 (d, 1H, J = 4.2Hz), 8.22 (d, 1H, J = 8.7Hz), 7.94 (d, 1H, J = 16.4Hz), 7.84-7.79 ( m, 1H), 7.68-7.50 (m, 4H), 7.40 (t, 1H, J = 8.1 Hz), 7.30-7.26 (m, 1H), 7.06 (s, 1H), 7.00 (dd, 1H, J = 8.8, 1.9 Hz), 6.87 (dd, 1H, J = 8.0,

1.9 Hz), 6.79 (S, 1H), 3.96 (s, 3H), 2.17 (s, 3H), ESIMS m / z 451 [M + H] ⁺ . Anal calcd for C 26 H 22 N ₆ O ₂ x 0.5 H ₂ O x 0.4 hexane (494.0 g / mol): C, 69.05, H, 5.84, N, 17.01. Found: C, 68.78, H, 5.55, N, 17.05.

Example 58

6- [3 - ((l-ethyl-3-methyl-lH-pyrazol-5-yl) carboxamido) phenoxy] -3-E [2- (lH-imidazol-2-yl) ethenyl] -lH-indazole

A solution of 7.5 mL (7.5 mmol, 15.0 eq.) 1.0 M tetrabutylammonium fluoride in THF and 0.33 mL (5.0 mmol, 10 eq.) 1,2-diaminoethane was added to 360 mg (0.5 mL). mmol, 1.0 eq. [2-Methyl-5- (1- (2-trimethylsilanylethoxymethyl) -3 - {(E) -2- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] vinyl} 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid-1H-indazol-6-yloxy) -phenyl] -amide in 5 ml of 1,4-dioxane and the reaction mixture was heated at 90 ° C for 18 hours. At the end of this time, the reaction was concentrated under reduced pressure and the resulting orange oil was diluted with 50 mL of ethyl acetate. The organic layer was washed thoroughly with 5 x 50 mL saturated sodium bicarbonate, brine, dried over magnesium sulfate and concentrated under reduced pressure to give 287 mg of a yellow solid. raw

The 349 product was purified by ring-plate chromatography on silica gel using 5% methanol-chloroform with 0.1% ammonium hydroxide (R _f 0.1) as eluent to give 140 mg (61%) (5- {3 - [( E) 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid 2- (1H-imidazol-2-yl) vinyl] -1H-indazol-6-yloxy} 2-methylphenyl) amide as a pale yellow solid: HPLC R t = 11.8 min, TLC R f = 0.8 (10% methanol-chloroform with 0.1% ammonium ^hydroxide); H NMR (300 MHz, _DMSO-d6) δ 13.03 (s, 1 H 12.30 (bs, 1H), 9.78 (s, 1H), 8.00 (d, 1H, J = 8.6 Hz), 7.54 (d, 1H, J = 16.8) Hz), 7.32 (d, 1H, J = 8.5 Hz), 7.27 (d, 1H, J = 16.9)

Hz), 7.13-7.12 (m, 3H), 7.00-6, 94 (m, 3H), 6.78 (s, 1H), 4.39 (q, 2H, J = 7, 1 Hz), 2.23 (s, 3H), 2.19 (s, 3H), 1.28 (t, 3H, J = 7.1 Hz). Túial. calculated for C 26 H 25 N ₇ O ₂ · 0.5 H ₂ O · 0.4 hexane (511.0 g / mol): C, 66.75, H, 6.23, N, 19.19. Found: C, 66.95, H, 6.25, N, 18.83.

The starting materials were prepared as follows:

(i) Preparation of 1- (2-trimethylsilanylethoxymethyl) -1H-imidazole

2.0 g (29.4 mmol, 1.0 eq) of ΙΗ-imidazole in 70 mL of THF was added at 0 ° C to a suspension of 1.5 g (38.2 mmol, 1.3 eq) of sodium hydride (60% in mineral oil) in 30 mL THF. After gas evolution ceased, the mixture was warmed to room temperature for 45 minutes and then cooled to 0 ° C again. 5.4 ml (30.2 mmol, 1.0 eq.) Of [2- (trimethylsilyl) ethoxy] methyl chloride were added and the mixture was warmed to room temperature overnight. The reaction was quenched with saturated sodium bicarbonate, THF was removed under reduced pressure, and the resulting beige suspension was extracted with ethyl acetate. The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated to give 6.9 g of an amber oil.

350

The oil was purified by flash chromatography on silica gel using 2% methanol / chloroform as eluent to give 4.7 g (81%) of 1- (2-trimethylsilanylethoxymethyl) -1H-imidazole as a pale amber oil: TLC Rf = 0.3 (5% methanol / chloroform), ¹ H NMR (300 MHz, DMSO-dg) δ

7.77 (s, 1 H), 7.26 (d, 1 H, J = 1.2 Hz), 6.93 (s, 1 H), 5.32 (s, 2 H), 3.45 (t, 2 H) J = 8.0 Hz), 0.83 (t, 2H, J = 8.0 Hz), -0.05 (s, 9H), ¹³ C NMR (75 MHz, DMSO-d 6) δ 137, 9 , 128, 8, 119, 6, 74,

65.1, 17.1, -1.4.

(ii) Preparation of (1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl) methanol

3.0 g (15.4 mmol, 1.0 eq.) Of 1- (2-trimethylsilanylethoxymethyl) -ΙΗ-imidazole was dissolved in 150 mL of THF and cooled to -78 ° C. Add 10.6 mL (16.9 mmol, 1.1 eq.) Of n-BuLi, 1.6 M in hexane, and allow the temperature to rise to -40 ° C for 15 minutes. The light yellow solution was stirred for an additional 30 minutes at -40 ° C, then the anion was quenched with 1.3 mL (16.9 mmol, 1.1 eq) DMF. The reaction mixture was warmed to room temperature overnight and then quenched with water. The solvent was removed and the mixture was extracted with dichloromethane. The organic layer was washed with water, dried over brine and magnesium sulfate, filtered and concentrated to give 3.5 g of crude product, TLC Rf = 0.5 (5% methanol / chloroform). By proton NMR spectrum of the aldehydic proton at 9.73 ppm is present (300 MHz, _DMSO-d6). The crude product was dissolved in 15 mL of methanol, cooled to 0 ° C and treated with 1.2 g (30.8 mmol, 2.0 eq) of sodium borohydride. The reaction mixture was warmed to room temperature overnight. The solvent was removed and

Μ

The crude product was diluted with chloroform, washed with water, dried over brine and magnesium sulfate, filtered and concentrated to give 3.6 g of a clear oil. The oil was purified by flash chromatography on silica gel using a 3-6% methanol / chloroform / 0.1% ammonium hydroxide mixture as eluent to give 1.4 g (41%, 2 steps) [1- (2-trimethylsilanylethoxymethyl) -1H imidazol-2-yl] methanol as a white solid: TLC = 0.4 (8% ^{methanol-chloroform);} H NMR (300 MHz, DMSO-de) δ 7.22 (d, 1 H, J = 1 1 Hz), 6.81 (d, 1H, J = 1.0 Hz), 5.36 (s, 2H), 5.31 (brt, 1H, J = 5.2 Hz), 4.50 (d, 2H, J = 4.8Hz), 3.48 (t, 2H, J = 8.0Hz), 0.83 (t, 2H, J = 8.0Hz), -0.05 ( s, 9H), ¹³ C NMR (75 MHz, DMSO-d 6) δ 148, 9, 127, 8, 122.5, 75.5, 66, 5, 56, 9, 18, 5, 0, 0.

(iii) Preparation of 2-chloromethyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole hydrochloride

HCl

A solution of 0.87 mL (12.0 mmol, 3.0 eq) of thionyl chloride in 8 mL of chloroform was cooled to 0 ° C and treated with a solution of 0.92 g (4.0 mmol, 1.0 eq) [1 - (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] methanol in 2 ml of chloroform. The clear solution was stirred at 0 ° C for 30 minutes and then at room temperature for 2 hours. The solvent was removed and the product was gradually suspended and concentrated using chloroform, toluene and cyclohexane to give 1.1 g (97%) of 2-chloromethyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole hydrochloride as a beige solid: ^X H NMR (300 MHz, DMSO-d 6) δ 7.85 (d, 1H, J = 1.9 Hz), 7.70 (d, 1H, J = 1.9 Hz),

5.62 (s, 2H), 5.14 (s, 2H), 3.57 (t, 2H, J = 8.3 Hz), 0.90 (t,

352

2Η, J = 8.3 Hz), -0.02 (s, 9H), ¹³ C NMR (75 MHz, DMSO-d 6) δ 142, 1, 123, 2, 120, 2, 76, 5, 66, 8, 31, 7, 17.3, -1.4.

(iv) Preparation of 3-amino-4-methylphenol v

nh ₂

Black solid (95%), HPLC R t = 4.4 min, ¹ H NMR (300 MHz, DMSO-d 6) δ 8.61 (s, 1H), 6.64 (d, 1H, J = 8.1 Hz);

6.05 (d, 1H, J = 2.4 Hz), 5.8 (dd, 1H, J = 8.0, 2.4 Hz),

4.64 (bs, 2H), 1.92 (s, 3H), ¹³ C NMR (75 MHz, DMSO-d ₆ ) δ 156.1, 147.2, 130.2, 111.7, 103, 3, 101.1, 16.6.

(v) Preparation of 3- (benzhydrylidenamino) -4-methylphenol

Yellow solid (49%), mp 106-108 ° C, HPLC R t = 15.3 min, TLC R f = 0.2 (10% ethyl acetate / cyclohexane), ¹ H NMR (300 MHz, DMSO-d 6) δ 8.91 (s, 1H), 7.77-7.56 (m, 2H), 7.53-

7.43 (m, 3H), 7.35-7.31 (m, 3H), 7.13-7.10 (m, 2H), 6.82 (d, 1H, J = 8.3 Hz) 6.22 (dd, 1H, J = 8.1, 2.5 Hz), 5.88 (d, 1H, J = 2.5 Hz), 1.97 (s, 3H), ¹³ C NMR ( 75 MHz, DMSO-de) δ 165.4,

155, 2, 150, 6, 138, 9, 136, 0, 130, 8, 130, 2, 128.7, 128, 4, 128.2, 128.0, 1173, 109, 9, 106, 2, 17.0.

(vi) Preparation of benzhydrylidene- (2-methyl-5- [3 - ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazol-6-yloxy] phenyljamine

353

A round bottom flask was charged with 5.5 g (26.0 mmol, 2.0 eq.) Of potassium phosphate, 3.9 g (13.6 mmol, 1.1 eq.) Of 3- (benzhydrylideneamino) -4- methyl phenol, 6.2 g (13.0 mmol, 1.0 eq.) of 6-iodo-3 - ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazole and 130 mL of o-xylene. The resulting suspension was degassed, bubbled with argon and treated with 916 mg (1.1 mmol, 8 mol%) of a mixture of tris (dibenzylideneacetone) dipalladium (0) and 656 mg (2.2 mmol, 16 mol%) of biphenyl-2-yl- di-tert-butyl-phosphane. The flask was immersed in an oil bath stirred at 100 ° C for 18 hours. The black suspension was cooled to room temperature, filtered through celite, and concentrated. The black oil was dissolved in chloroform, washed with water, brine, dried over magnesium sulfate, filtered and concentrated to give 12.1 g of a black oil. The crude product was purified by flash chromatography on silica gel using 10-15% ether / cyclohexane as eluent to give 1.4 g (16%) of benzhydrylidene- {2-methyl-5- [3 - ((E) styryl) - 1- (2-trimethylsilanylethoxymethyl) -1H-indazol-6-yloxy] phenyl} amine as a yellow ether foam: HPLC R t = 24.3 min, TLC R _f = 0.5 (20% ether / cyclohexane), ¹ 1 H NMR (300 MHz, DMSO-d 6) δ 8.10 (d, 1H, J = 8.8 Hz), 7.75-7.66 (m, 4H), 7.53-7.31 (m, 11H), 7.14-7.08 (m, 4H),

6.62 (dd, 1 H, J = 8.8, 2.0 Hz), 6.55 (dd, 1 H, J = 8.2, 2.5 Hz), 6.20 (d, 1 H, J = 2.4 Hz), 5.64 (s, 2H), 3.51 (t, 2H, J =

7.8 Hz), 2.12 (s, 3H), 0.78 (t, 2H, J = 7.7 Hz), -0.14 (s, 9H).

354 (vii) Preparation of 2-methyl-5- [3 - ((E) styryl) -1- (2-trimethylsilanylethoxymethyl-1H-indazol-6-yloxy) phenylamine

Amber oil (80%), HPLC Rt = 21.0 min, TLC Rf = 0.4 (20% ethyl acetate / cyclohexane), ¹ H NMR (300 MHz, DMSO-d 6) δ 8.18 (d, 1H, J = 8.8 Hz), 7.74-7.71 (m, 2H), 7.52 (s, 2H), 7.43-7.38 (m, 2H), 7.33-7.28 (m, 1H), 7.20 (d, 1H, J = 2.0 Hz), 6.77-6, 90 (m, 2H), 6.33 (d, 1H, J = 2.4 Hz) , 6.16 (dd,

1H, J = 8.0, 2.5 Hz), 5.66 (s, 2H), 5.01 (bs, 2H), 3.52 (t, 2H, J = 8.0 Hz), 2 0.03 (s, 3H), 0.80 (t, 2H, J = 8.0 Hz), -0.11 (s, 9H).

(viii) Preparation of 2-Ethyl-5-methyl-2H-pyrazole-2-methyl-5- [3 - ((E) styryl) -1- (2-trimethylsilanylethoxymethyl) -1H-indazol-6-yloxy] phenyl} amide 3-carboxylic acid

The white foam (85%), HPLC R t = 21.5 minutes, TLC _Rf 0.2 (20% ethyl acetate-cyclohexane); ^1H NMR (300 MHz, DMSO-de) δ

9.75 (s, 1H); 8.24 (d, 1H, J = 8.8 Hz); 7.74-7.72 (m, 2H);

7.53 (s, 2H), 7.43-7.38 (m, 2H), 7.34-7.28 (m, 3H), 7.12 (d, 1H, J = 2.6 Hz) 7.00 (dd, 1H, J = 8.8, 2.0 Hz), 6.92 (dd, 1H,

355

J = 8.3, 25 Hz), 6.78 (s, 1H), 5.69 (s, 2H), 4.40 (q, 2H, J =

7.1 Hz), 3.53 (t, 2H, J = 7.9 Hz), 2.22 (s, 3H), 2.19 (s, 3H),

1.27 (t, 3H, J = 7.1Hz), 0.78 (t, 2H, J)

7.9 Hz), -0.15 (S, (ix) Preparation of 2-Ethyl-5 {5- [3-formyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazol-6-yloxy] -2-methyl-phenyl} -amide 3-methyl-2H-pyrazole-3-carboxylic acid

A solution of 774 mg (1.28 mmol, 1.0 eq) of 2-ethyl- (2-methyl-5- [3 ((E) styryl) - (2-trimethylsilanylethoxymethyl) -1H-indazol-6-yloxy) phenyl} amide 5-Methyl-2H-pyrazole-3-carboxylic acid in 8 mL 1,4-dioxane and 2 mL water was treated with 7 mg (0.03 mmol, 0.02 eq.) Of osmium tetroxide. The solution was stirred for 5 minutes and then treated with 822 mg (3.84 mmol, 3.0 eq) of sodium periodate. The resulting thick yellow-brown suspension was stirred overnight at room temperature, poured into 100 mL of 15% Na ₂ S ₂ O 3 and extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated to give 902 mg of an amber oil. The crude product was purified by ring-plate chromatography on silica gel using 10-50% ethyl acetate-cyclohexane as eluent to give 590 mg (86%) of [5- [3-formyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazole-6- 2-Ethyl-5-methyl-2H-pyrazole-3-carboxylic acid yloxy] -2-methyl-phenyl} -amide as a beige solid from ether: HPLC R t = 18.9 min, TLC R f = 0.2 (40% ethyl acetate) and cyclohexane), ¹ H

356

NMR (300 MHz, DMSO-de) δ 10.16 (p , 1H, 9.75 (s, 1 H), 8.14 (d 1H, J = 8.8 Hz), 7.48 (d, 1 H, J = 1.8 Hz), 7.32 (d, 1 H, J = 8, 5 Hz), 7.16-7.13 (m, 2H), 6.93 (Dd, 1H, J = 8.3, 2.6 HZ) 6.78 (with, 1H), 5.84 (s, 2H), 4.39 (q, 2H) J = 7.1 Hz), 355 (t 2H, J = 7.8 Hz), 2.23 (s, 3H), 2, 19 (s, 3H), 1.27 (t, 3H, J 7.2 Hz), 0.79 (t, 2H, J) = 7.8 Hz), -0.15 (S, 9H).

(x) Preparation of 2-methyl-5- (1- (2-trimethylsilanylethoxymethyl) -3 ((E) -2- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] vinyl} -1H-indazole-6 -yloxy) phenyl] amide 2-ethyl-5-methyl-2H-pyrazole-3-carboxylic acid

A solution of 344 mg (1.22 mmol, 2.0 eq) of hydrochloride

2-Chloromethyl-1- (2-trimethylsilanylethoxymethyl) -1H-imidazole in 20 mL of chloroform was converted to the free base form with saturated sodium bicarbonate. The organic layer was dried over brine and magnesium sulfate, filtered and concentrated to give 301 mg (100%) of an amber oil. The resulting oil was dissolved in 12 mL of acetonitrile, treated with 304 mg (1.16 mmol, 1.9 eq) of triphenylphosphine and heated at 70 ° C for 18 hours. The solvent was removed and the crude 1- (2-trimethylsilanylethoxymethyl) -2 - [(triphenyl-η ⁵ -phosphanyl) methyl] -1H-imidazole chloride was dissolved in 12 mL of THF cooled to 78 ° C and treated with 1.2 mL (1, 22 mmol, 2.0 eq) of potassium tert-butoxide, 1.0 M in THF. After 15 minutes 325 mg (0.61 mmol, 1.0 eq) of {5- [3-formyl-1- (2-trimethylsilanylethoxymethyl) -1H-indazol-6-yloxy] -2-methylphenyl} amide 2 was added -

357 ethyl-5-methyl-2H-pyrazole-3-carboxylic acid in 1 mL of THF to the ylide at -78 ° C. The clear yellow solution was warmed to room temperature overnight, quenched with water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered and concentrated to give 1.0 g of crude product as an amber oil. The crude product was purified by further round-plate chromatography on silica gel using 0-5% methanol-chloroform as eluent to give 390 mg (88%) of [2-methyl-5- (1- (2-trimethylsilanylethoxymethyl) -3- { 2-Ethyl- (E) -2- [1- (2-trimethylsilanylethoxymethyl) -1H-imidazol-2-yl] vinyl} -1H-indazol-6-yloxy) phenyl] amide

5-methyl-2H-pyrazole-3-carboxylic acid as a tan solid after standing overnight: HPLC R t = 20.6 min, TLC R f =

0.4 (4% mixture hurling nolu and dichloromethane), ² h: NMR (300 MHz DMSO · -d ₆ ) δ 9.75 (with, 1H), 8.14 (d, IH, J) = 8, 8 Hz) , 7.64 (d, 1H, J = 16.2 Hz), 7.42 (D, 1 H, J = 16.3 Hz), 7.39 -7.35 (M, 3H), 7, 30 (d, 1 H, J = 8, -5 Hz) 7.12 (d, 1 H, J = = 2.5 Hz), 7, 03 (with, 1H), 6.99 (dd, 1H, J = 8.8, 1.9 Hz), 6, 78 (with, 1H), 5.70 (with, 2H), 5.55 (s, 2H); 4.40 (q, 2H, J = 7.1 Hz); 3, 55 -3, 48 (M, 4H), 2.22 (s, 3H), 2.19 (s, 3H) 1.27 (T, 3H, J = 7.1 Hz), 0, 84 (t, 2H, J) = 7, 9 Hz) 0.77 (t, 2H) J = 7.9 Hz), -0, 11 (with, 9H), -0.15 (s, 9H).

Example 59 (a)

6- (3 - ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole hydrochloride

358

4.57 g (9.59 mmol, 1 eq.) Of Example 41 (a) was taken up in 96 mL of methanol and protected from light with an aluminum foil. A second flask with 20 ml of methanol was treated

684 μΐ (1.00 eq) acetyl chloride for 5 minutes. The acid solution was then added to the first mixture and the mixture was washed several times with ~ 20 mL of methanol.

The volatile material was removed under reduced pressure and the residue was triturated

1: 1 mixture of ethyl acetate and hexane to give 4.82 g (98%) of a yellow powder after filtration and drying: analyzed with 1.0 H ₂ O, calculated: C (61.85), H (5.07), N (15.46). Found: C (61.15), H (5.15), N (15.38).

Example 59 (b)

6- [3 - ((1,3-Dimethyl-1H-pyrazol-5-yl) carboxamido) benzoyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole hydrochloride

Example 59 (b) was prepared in a similar manner to Example 59 (a) except that Example 41 (p) was used instead of Example (a). HPLC: 3.92 minutes (100% ^area); H NMR (DMSO) δ 10.45 (s, IH), 8.85 (d, IH, J = 4.8 Hz), 8.49 (d, 1H, J = 8.7 Hz), 8.38-8, 30 (m, 4H), 8.21 (dt, 1H, J = 7.5, 2.1 Hz), 8.01 (s, 1H 7.80-7.79 (m, 2H), 7.72-7.64 (m, 3H), 6.70 (s, 1H), 4.30 (s, 3H), 2.33 (s) s, 3H). Anal. (C 27 H ₂₀ N ₄ 0 ₂ S · 1.3 H ₂ O · 0.2 EtOAc):

calculated C, 62.15, H, 5.18, N, 15.64, measured C, 61.81, H,

5.01, N, 15.64.

359

Example 59 (c)

6- [N- (5 - ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) -2-fluoro-4-methylphenyl) amino] -3-E- [2- (pyridine) hydrochloride 2-yl) ethenyl] -lH-indazole

was an example of

Compound prepared in a manner similar to Example 48 (a)

41 (a). Anal, calculation:

Example except that the compound was used instead

C, 63.21; H, 5.12;

N, 38.43, from Example

Cl, 6.66.

Found: C, 60.86, H,

5.38, N, 17.28, Cl,

6.52.

Example 59 (d)

6- [N- (3 - ((1,3-dimethyl-1H-pyrazol-5-yl) carboxamido) -4-fluorophenyl) amino] -3-E- [2- (pyridin-2-yl) ethenyl hydrochloride ] -1Hindazolu

I-VXX / L . .HCl Example compound 59 (d) was prepared similarly way as in the example 59 (a) except that the compound from the example 49 (a) was used in place of the example compound

(A). ^X H NMR (300 MHz, DMSO-d?) 13.2 (b, 1H), 9.97 (s, 1H).

8.75 (d, 1H, J = 5.44 Hz), 8.51 (bs, 1H), 8.35 (m, 2H), 8.20 (d, 1H, J = 16.59 Hz) 8.06 (d, 1H, J = 8.81 Hz), 7.71 (d, 1H,

360

J = 16, 59 Hz), 7.70 (m, 1H) 7.44 (dd, 1H, J = 6.65Hz) J = 2, 67 Hz), 7.24 (t, 1 H, J = 9.54 Hz), 7.12 (d, 1H, J = 1.46 HZ), 7.05 (m, 2H) 6.86 (with, 1H), 4.0 (s, 3H), 3.84 (bs, 1H,

2.20 (s, 3H).

Example 59 (e)

6- [3 - ((1-ethyl-3-methyl-1H-pyrazol-5-yl) carboxamido) phenoxy] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole hydrochloride

Compound from the method of Example 31 (d)

An example of an example was used instead

59 (a) except prepared by a similar compound of the compound of the example

41 (a ). ^X H NMR (DMSO SO-d ₆ ) δ 13.53 (s, 1H) 10.23 (s, 1H). 8.78 (D, 1 H, J = 5.5 H z), 8.30 (m, 4H) 7.80 (m, 2H), 7.59 (d, 1H, J = 7.7 Hz), 7.55 (s, 1 H), 7.41 (t, 1H, J = 8.1 Hz), 7.11 (with, 2H), 6.88 (d, 1 H, J = 6.7 Hz), 6.81 (with, 1H), 4.38 (q, 2H, J = 7.0 Hz), 3.75 (b s, 1H) 2.19 (s, 3H), 1.29 (t, 3 H, J = 7.0

H ₂ 0

C, • 0.1 EtOAc:

Hz). Anal. Calcd. For C27H25ClN6O2 · 1.7

H, 5.45; N, 15.55. Measured: C,

60.88.

H,

5.51;

N,

15.27.

Example 59 (f)

6- [2- (Methylcarbamoyl) phenylsulfanyl] -3-E- [2 (pyridin-2-yl) ethenyl] indazole hydrochloride

361

(F)

The compound of the Example was prepared in a similar manner to Example (a) except that the compound of Example 33 (a) was used in place of the Example compound

41 (a). Analyzed with 2.0 H ₂ O, calculated C, 57.58, H, 5.05, N,

12.21, Cl, 6.99. Found: C, 57.24; H, 5.048; N, 11.91: Cl,

6, 63.

Examples of the compounds described above can be tested for activity using the assays described below.

Biological testing: enzyme tests

Stimulation of cell proliferation by growth factors such as VFFG, FGF and others depends on their induction of autophosphorylation of each of their respective receptor tyrosine kinases. Thus, the ability of a protein kinase inhibitor to block autophosphorylation can be measured by inhibiting peptide substrates. The following constructs were designed to measure the protein kinase inhibitory activity of the compounds.

VEGF-R2 construct for test:

This construct investigates the ability of a test compound to inhibit tyrosine kinase activity. The human vascular endothelial growth factor receptor 2 receptor (VEGF-R2A50) (VEGF-R2A50) construct (VEGF-R2) lacking 50 central residues of the 68 rest of the insertion kinase domain was expressed in a baculovirus / insect cell system. From 1356

The 362 residues of complete VEGF-R2 contain VEGF-R2A50 residues 806 to 939 and 990 to 1171, as well as one point mutation (E990V) in the insertion kinase domain relative to the wild-type VEGF-R2. Autophosphorylation of the purified construct was performed by incubating the enzyme at 4 μΜ in the presence of 3 mM ATP and 40 mM MgCl 2 in 100 mM HEPES, pH 7.5, containing 5% glycerol and 5 mM DTT, at 4 ° C for 2 hours. After autophosphorylation, this construct has been shown to have catalytic activity substantially identical to the construct containing the autophosphorylated wild-type kinase domain (see Parast et al., Biochemistry, 37, 16788-16801, 1998).

FGF-R1 construct for test:

The intracellular kinase domain of human FGF-R1 was expressed using a baculovirus vector expression system starting with the endogenous methionine residue 456 to glutamate 766, according to the residue numbering system of Mohammadi et al. (Mol. Cell. Biol., 16, 977-989, 1996). In addition, the construct also has the following 3 amino acid substitutions: L457V, C488A and C584S.

LCK construct for test:

LCK tyrosine kinase was expressed in insect cells as an N-terminal deletion starting from amino acid residue 223 to the end of the protein at residue 509, with the following two amino acid substitutions in the N-terminal portion: P233M and C224D.

CHK1 construct for test:

363

Complete human CHK1 (FL-CHK1) with His tag at the C-terminal portion was expressed using a baculovirus / insect cell system. It contains 6 histidine residues (6 x His tag) in the C-terminal portion of 476 amino acids of human CHK1. The protein was purified by conventional chromatographic techniques.

CDK2 / cyclin A construct for assay:

CDK2 was purified using a published method (Rosenblatt et al., J. Mol. Biol., 230, 1317-1319, 1993) from insect cells that had been infected with a baculovirus expression vector. Cyclin A was purified from E. coli cells expressing full-length recombinant cyclin A, and the truncated A cyclin A construct was created by limited proteolysis and purified as described previously (Jeffrey et al., Nature, 376, 313-320, 1995).

CDK4 / cyclin D construct for test:

The human CDK4 and cyclin D3 complex, or the complex of cyclin D1 and the human CDK4 and glutathione-S-transferase (GST-CDK4) fusion protein, was purified using traditional biochemical chromatographic techniques from insect cells that were simultaneously infected (coinfected) with the corresponding baculovirus expression vectors. .

FAK test construct:

The human FAK catalytic domain (FAKcd409) was expressed using a baculovirus vector expression system. The expressed 280 amino acid domain contains methionine residues 409 to glutamate 689. There is one amino acid substitution (P410T) relative to the access

364 of sequence number L13616, published by Whithey, G.S. Et al. (DNA Cell Biol, 9, 823-30, 1993). The protein was purified using a classical chromatography technique.

TIE-2 (TEK) construct for test:

The TIE-2 tyrosine kinase domain was expressed in insect cells as an N-terminal deletion starting from amino acid residue 774 to the end of the protein at residue 1124. This construct also carries a R774M mutation that serves as a translation initiation methionine residue.

VEGF-R2 test

Coupled spectrophotometric (FLVK-P) test

The production of ADP from ATP that accompanies phosphate transfer was associated with NADH oxidation using phosphoenolpyruvate (PEP) and a pyruvate kinase (PK) and lactate dehydrogenase (LDH) system. Oxidation of NADH was monitored by a decrease in absorbance at 340 nm (β34ο = 6.22 cm ^-1 mM ^-1 ) using a Beckman DU 650 spectrophotometer. Test conditions for phosphorylated VEGF-R2A50 (designated as FLVK-P in the tables below) were as follows: 1mM PEP, 250μΜ NADH, 50 units LDH / ml, 20 units PK / ml, 5mM DTT, 5mM poly (E ₄ Yi), 1mM ATP and 25mM MgCl ₂ in 200mM HEPES, pH 7.5. The assay conditions for non-phosphorylated VEGF-R2A50 (designated as FLVK in the tables) were as follows: 1mM PEP, 250μΜ NADH, 50 LDH / ml units, 20 PK / ml units, 5mM DTT, 20mM poly (E ₄ Yi), 3mM ATP and 60mM MgCl ₂ and 2 mM MnCl ₂ in 200 mM HEPES, pH 7.5. Assays were initiated with 5 to 40 nM enzyme. K i values were determined by measuring enzyme activity in the presence of varying concentrations of test compound. Data were analyzed using the Enzyme Kinetic and Kaleidagraph software.

365

ELISA

Phosphogastrin formation was monitored using the biotinylated gastrin peptide (1-17) as substrate. Biotinylated phosphogastrin was immobilized using streptavidin-coated 96 well microtiter plates, followed by detection using an anti-phosphotyrosine antibody conjugated with horseradish peroxidase. Horseradish peroxidase activity was monitored using the 2,2'-azinodi [3-ethylbenzathiazoline sulfonate (6)] diammonium salt (ABTS). Typical assay solutions included: 2μΜ biotinylated gastrin peptide, 5 mM DTT, 20μΜ ATP, 26 mM MgCl 2 and 2 mM MnCl 2 in 200 mM HEPES, pH 7.5. The assay was initiated with 0.8 nM phosphorylated VEGF-R2A50. Horseradish peroxidase activity was tested using 10 mM ABTS. The horseradish peroxidase reaction was stopped by addition of acid (H 2 SO 4), followed by absorbance reading at 405 nm. Ki values were determined by measuring enzyme activity in the presence of varying concentrations of test compound. Data were analyzed using the Enzyme Kinetic and Kaleidagraph software.

FGF-R test

The spectrophotometric assay was performed as described above for VEGF-R2, except for the following concentration changes: FGF-R = 50 nM, ATP = 2 mM and poly (E4Y1) = 15 mM.

LCK test

The spectrophotometric assay was performed as described above for VEGF-R2, except for the following concentration changes: LCK = 60 nM, MgCl ₂ = 0 mM, poly (E4Y1) = 20 mM.

366

Test CHK1

The production of ADP from ATP that accompanies phosphate transfer to the synthetic substrate peptide Syntide-2 (PLARTLSVAGLPGKK) was coupled with NADH oxidation using phosphoenolpyruvate (PEP) through the action of pyruvate kinase (PK) and lactate dehydrogenase (LDH). NADH oxidation was monitored by a decrease in absorbance at 340 nm (e340 = 6.22 cm ^-1 mM ^-1 ) using an HP8452 spectrophotometer. Typical assay solutions included: 4mN PEP, 0.15mM NADH, 28 LDH / ml units, 16 PK / ml units, 3mM DTT, 0.125mM Syntide-2, 0.15mM ATP, 25mM MgCl ₂ in 50mM TRIS, pH

7.5 and 400 mM NaCl. Assays were initiated with 10 nM FL-CHK1. K i values were determined by measuring the initial enzyme activity in the presence of varying concentrations of test compounds. Data were analyzed using the Enzyme Kinetic and Kaleidagraph software.

CDK2 / cyclin A and CDK4 / cyclin D assays

Cyclin-dependent kinase activity was measured by quantification of enzyme-catalyzed, time-dependent incorporation of [ ³² P] ATP radioactive phosphate into a recombinant fragment of retinoblastoma protein. Unless otherwise indicated, assays were performed in 96-well plates in a total volume of 50 μΐ, in the presence of 10 mM HEPES (N- [2-hydroxyethyl] piperazine-N '- [2-ethanesulfonic acid]) (pH 7.4) , lOmM _MgCl2, 25μΜ adenosine triphosphate (ATP), 1 mg / mL ovalbumin, 5 μς / πιΐ leupeptin, lmM dithiothreitol lOmM recombinant β-glycerophosphate, 0 mM vanadate, mM sodium fluoride, 2.5 mM ethylene glycol-bis (β -aminoethyl ether) -N, N, N ', N'-tetraacetic acid (EGTA), 2% (v / v) dimethylsulfoxide and 0.03 to 0.2 µϋ [ ³² P] ATP. The substrate (0.3-0.5 µg) was purified fragment

367 retinoblastoma protein (Rb) (residues 386-928 of native retinoblastoma protein, 62.3 kD, containing most of the phosphorylation sites detected in the native protein of 106 kD, and those mark six histidine residues for easy purification). Reactions were initiated with CDK2 (150 nM CDK2 / cyclin A complex) or CDK4 (50 nM CDK4 / cyclin D3 complex), incubated at 30 ° C and terminated after 20 minutes by adding ethylenediaminetetraacetic acid (EDTA) to a concentration of 250 mM. The phosphorylated substrate was then captured on a nitrocellulose membrane using a 96-well plate filter and the unincorporated radioactivity was removed by repeated washing with 0.85% phosphoric acid. Radioactivity was quantified by exposure to dry nitrocellulose membrane using a Phosphoimager imaging device. The apparent Ki values were measured by assaying enzyme activity in the presence of various concentrations of the compound and subtracting background radioactivity measured without enzyme. Kinetic parameters (kcat, Km for ATP) were measured for each enzyme under usual test conditions by determining the dependence of the initial velocities on the ATP concentration. Data were translated by competitive inhibition using Kaleidagraph software (Synergy Software) or by data by competitive inhibition by tight binding using KineTic software (BioKin, Ltd.). The measured Ki values for the known inhibitors of CDK4 and CDK2 were consistent with the published IC50 values. The specific activity of CDK4 was the same, either in complex with the construct of complete cyclin D3 or truncated cyclin D3, both complexes also gave very similar Ki values for selected inhibitors.

Test FAK

A fluorescence polarization assay provided by LJL Biosystems was used for FAK HTS. The kinase reaction contained:

368 100 mM Hepes pH 7.5, 10 mM MgCl ₂ , 1 mM DTT, 1 mM ATP and 1 mg / ml poly Glu-Tyr (4: 1). The reaction was initiated by the addition of 5 nM FAKcd409. The reaction was terminated by the addition of EDTA, followed by the addition of a fluorine-labeled peptide and an anti-phosphotyrosine antibody provided by LJL Biosystems. The inhibition results were read on an Analyst (LJL) detector.

TIE-2 spectrophotometric test

The kinase-catalyzed production of ADP from ATP that accompanies phosphate transfer to a random poly (Glu ₄ Tyr) copolymer was coupled to NADH oxidation using pyruvate kinase (PK) and lactate dehydrogenase (LDH) activity. NADH conversion to NAD ⁺ was monitored by decrease in absorbance at 340 nm (ε - 6.22 cm mM ^-1 ) using a Beckman DU650 spectrophotometer. Typical reaction solutions contained 1 mM phosphoenolpyruvate, 0.24 mM NADH, 40 mM MgCl ₂ , 5 mM DTT, 2.9 mg / ml poly (Glu ₄ Tyr), 0.5 mM ATP, 15 units / ml PK, 15 units / ml LDH at 100mM HEPES, pH 7.5. Assays were initiated by the addition of 4-12 nM phosphorylated Tie-2 (aa 775-1122). Percent inhibition was determined in triplicate at ΙμΜ inhibitor level.

TIE-2 DELFIA test

Phosphotyrosine formation was monitored by using biotinylated p34cdc2 (aa 6 to 20 = QUEKIGEGTYGWYK) peptide as substrate. The biotinylated peptide was immobilized using NeutrAvidin ™ coated 96 well microtiter plates, followed by detection using an anti-phosphotyrosine (PY20) antibody conjugated with europium N1 chelate. Typical test solutions included: ΙμΜ biotinylated p34cdc2 peptide, 150μΜ ATP, 5mM MgCl ₂ , 1mM DTT, 0.01% BSA, 5% glycerol, 2% DMSO, 25mM HEPES, pH 7.5. Test was

369 initiated on a NeutrAvidin plate with 50 nM intracellular domain of TIE2. The kinase reaction was terminated with 50 mM EDTA. Plates were then washed and Europe antibody was added. After incubation, the plates were washed again and DELFIA ™ enhancement solution was added. Plates were read in standard settings for europium detection (ex 340 nm, em 615 nm, missed 400 μεεο, window 400 μεεε). Percent inhibition was calculated using plate reference wells to which DMSO was added and not the compound in DMSO, and the background was subtracted from both experimental and control wells relative to the plate reference wells to which EDTA was added prior to enzyme addition.

HUVEC cell proliferation assay

This assay determined the ability of a test compound to inhibit growth factor-stimulated proliferation of human umbilical vein endothelial cells ("HUVECs"). HUVEC cells (passage

3-4, Clonetics, Corp.) were thawed into EGM2 culture medium (Clonetics Corp) in T75 flasks. 24 hours later fresh EGM2 medium was added to the flasks. Four or five days later, the cells were exposed to additional culture medium (F12K medium supplemented with 10% fetal bovine serum (FBS), 60 μς / πιΐ endothelial cell growth supplement (ECGS) and 0.1 mg / ml heparin). Exponentially growing HUVECs were then used in experiments. Ten to twelve thousand HUVEC cells were plated in 96-well plates in 100 μΐ rich culture medium (described above). Cells were allowed to attach for 24 hours in this medium. The medium was then aspirated and 105 µL of deficient ("fasting") medium (F12K + 1% FBS) was added to each well. After 24 hours, 15 μΐ of test reagent dissolved in 1% DMSO in deficient medium or in this vehicle alone was added to each

370 well treated, final

The DMSO concentration was 0.1%. One hour later, 30 μΐ was added

VEGF (30 ng / ml) in deficient medium to all wells except those containing untreated controls, the final VEGF concentration was ng / ml.

Cell proliferation was quantitated 72 hours later with MTT dye reduction, at which point cells were exposed for 4 hours with MTT (Promega Corp.)

The dye reduction was stopped by the addition of a stop solution (Promega Corp.) and the absorbance at

595 λ on a 96 well plate spectrophotometric reader.

IC ₅₀ values were calculated by fitting the A ⁵⁹⁵ reaction curve to different concentrations of the test agent, typically seven concentrations in steps of 0.5 log were used, with three replicate wells at each concentration. One or two concentrations (one well per concentration) were used to screen the compound library plates and the% inhibition was calculated from the following formula:

% inhibition = (control - test) = (control - starvation) where

Control = ⁵⁹⁵⁹⁵ when VEGF is present without test agent

Test = ⁵⁹⁵⁹⁵ when VEGF is present with the test agent

Starvation = A ⁵⁹⁵ when VEGF and absence of the test agent.

Carcinoma Cell Proliferation Assay (MV522)

The protocol for determining cell proliferation in cancer cells is similar to the assay used to evaluate HUVEC cells. Two thousand lung carcinoma cells (line MV522, obtained from the American Tissue Cultural Collection) were seeded in growth medium (RPMI1640 medium supplemented with 2 mM glutamine and 10% FBS). Cells were allowed to adhere after

371 for 1 day prior to addition of test agents and / or vehicles. Cells were treated simultaneously with the same test reagents used in the HUVEC assay. Cell proliferation was quantified by MTT dye reduction assay 72 hours after challenge with test agent. The total duration of the assay is 4 days versus 5 days for HUVEC cells because MV522 cells were not exposed to deficient medium (fasting).

PK test in mice

Pharmacokinetics (e.g., absorption and elimination) of drugs in mice were analyzed using the following experiment. Test compounds were formulated as a solution or suspension in 30:70 (PEG 400: acidified H ₂ O) vehicle or as a suspension in 0.5% CMC. This was administered orally (po) and intraperitoneally (ip) at variable doses to two different groups (n = 4) of female B6 mice. Blood samples were collected from the orbital vein at time points: 0 hours (pre-dose), 0.5 hours, 1.0 hour, 2.0 hours and 4.0 hours and 7.0 hours post-dose. Plasma was obtained from each sample by centrifugation at 2500 rpm for 5 minutes. Test compound was extracted from plasma by organic protein precipitation method. For each time-lapse, 50 µΐ of plasma was mixed with 1.0 mL of acetonitrile, vortexed (vortexed on a micro-shaker) for 2 minutes, and then centrifuged at 4000 rpm for -1-5- minutes to precipitate the protein and extract from the test compound. Then the acetonitrile supernatant (extract containing the test compound) was poured into new test tubes and evaporated on a hot plate (25 ° C) in N ₂ gas vapors. 125 μΐ of the mobile phase (60:40, 0.025M NH ₄ H ₂ PO ₄ + 2.5 ml / L TEA: acetonitrile) was added to each tube containing the dried extract of the test compound. The test compound was resuspended in the mobile phase by vortexing and others

The 372 protein was removed by centrifugation at 4000 rpm for 5 minutes. Each sample was poured into an HPLC vial to analyze the test compound on a Hewlett Packard 1100 instrument by HPLC with UV detection. From each sample, 95 μΐ was injected onto a C-18 reverse phase Phenomenex-Prodigy column, 150 x 3.2 mm, and eluted with a 45-50% acetonitrile gradient over 10 minutes. Plasma concentrations of test compound (pg / ml) were determined by comparison to a standard curve (peak area versus concentration in pg / ml) using known concentrations of test compound extracted from plasma samples as described above. Together with standards and unknowns, three quality control groups (n = 4) (0.25 pg / ml, 1.5 pg / ml, and 7.5 pg / ml) were tested to ensure consistency of assays. the standard curve had an R ² > 0.99 and quality controls were all at 10% of the expected values.

Quantified test samples were plotted for visual display using Kalidagraph software and their pharmacokinetic parameters were determined using WIN NONLIN software. Example 1 (a) gave the following results: 0.69 (mouse pK, AUC, ip, pg-h / ml), 0.33 (mouse pK, AUC, po, pg-h / ml).

Human Liver Microsome Test (HLM)

The metabolism of compounds in human liver microsomes was measured by LC-MS analytical assay procedures as follows. First, human liver microsomes (HLM) were thawed and diluted to 5 mg / ml with cold buffer, 100 mM potassium phosphate (KPO ®). Appropriate amounts of KPO ₄ buffer, NADPH recovery solution (containing B-NADP, glucose-6-phosphate, glucose-6-phosphate dehydrogenase and MgCl ₂ ) and HLM were preincubated in 13 x 100 mm glass tubes at 37 ° C for 10 minutes ( 3 tubes per test compound - three replicates). The test compound (final concentration of 5 µM) was added to each tube to make

373 initiated the reaction and was stirred by gentle vortexing, ‘tic followed by incubation at 37 ° C. At time points t = 0.2 hours, a sample of 250 μ odstrán was removed from each incubation tube into a separate 12 x 75 mm glass tube containing 1 ml of ice-cold acetonitrile with 0.05μΜ reserpine. Samples were centrifuged at 4000 rpm for 20 minutes to precipitate proteins and salt (Beckman Allegra 6KR, S / N ALK98D06, # 634). The supernatant was transferred to new glass mm and evaporated on a 12x SpeedVac evaporator vacuum tube. The samples were reconstituted at

200 μΐ of the mixture

0.1% formic acetonitrile (90/10) and vortexed acid and dissolution. polypropylene microcentrifuge tubes at 14000 x g for a period of time

The samples were then transferred thoroughly to separate and centrifuged in minutes (Fisher Micro 14, S / N M0017580).

(No. 1 to 3) at each time point (0 and 2)

For each replicate of hours), an aliquot was placed in one HPLC vial (6 total samples) for LC-MS analysis described below.

samples of each test compound pooled

Samples of pooled compounds were injected into an LCMS system consisting of a Hewlett-Packard HP1100 diode sensor HPLC and a Micromass Quattro II triple quadruple mass spectrometer operating in SIR positive electrospray mode (programmed to scan specifically the molecular ion of each test compound). The peak of the curve for each test compound was integrated at each time point. For each compound, the peak area at each time point (n = 3) was averaged and this mean peak area at 2 hours was divided by the mean peak area at 0 hours to obtain the percentage of test compound remaining at 2 hours.

The results of testing the compounds using various assays are summarized in the table below, where "%" indicates the percentage

374 inhibition at the indicated concentration, the values represent Ki (nM) or% inhibition at a compound concentration of 1 μΜ for * or 50 nM for ** unless otherwise noted. "NI denotes insignificant inhibition.

Table 1

EX FLVK r · FLVK -P ** Lck- P * CHK -1 * FGFp · CDK2 ♦ CDK4 • HUVEC IC50 (nM) HUVEC + album! nICSO nM MV522 1C50 (μΜ) % HLM excess 2 hours) 2 (b) 300 425 549 228 μΜ .2 200 8000 2 (c) 2600 50 μΜ 26 μΜ 1 (a) 0 _r 3 2 68 5.2 27 19 13 54 0.35 98 3 6 ₍ 6 65 37% 4.8 112 16 23 930 2.2 8 (a) 3.2 23 43% 530 42 > 100 μΜ > 100 μΜ > 1000 > 10 8 (b) 72 12% O 50 UM 2 (d) 3.7 43% 91 68 53 53 450 00:18 1 (c) M IN 46% 78 560 670 > 1000 > 10 2 (a) 40 61% 20 20 μΜ 610 1600 > 1000 0.58 1 (b) 2.2 1400 4000 1300 > 1000 > 10 8 (c) 2.6 16 34% > 10 000 > 100 μΜ > 100 μΜ 280 > 10 -9 (a) - -1-6- l £ 11 uu O / U 9 (b) 24 448 2 (0 40 5% β 20 UM 10 9 9100 > 700 > 10 20 (a) 29 12.7 200 9.4 52 20 (b) 1.6 8 23% 28% 8.2 ca.10 14 15 - - - 12% d 25 UM - _. . 7 18 1300 17 11 532 8 (d) 11 82 000 4 (a) 0.65 68% NI 15.4 NI 19% 3 30 6.3 35 23 IN 2.1 12% NI 14% NI 17% 9.5 106 5.7 74 21 4.6 > 700 11 12 34,000 22 (b) 0.63 1.2 21.5 4.8 8.5 22 (a) 0.22 0.2 12 > 10 22 (0 0.64 38 4 {b) 2.7 1.9 13% & 1 μΜ 4.9 25 205 3.2 63 12 (a) L ⁸ 6.9 17% 19 6 87 2.1 59

375

12 (b) 0.48 1.8 32% 31 4.8 44 > 10 29 18 12 _r 5 19 (b) 0.49 6.6 58% Nl 60% Nl 11% 2Z9 27 4.3 137 19 (a) OO 6.8 16% 1 1 μΜ 92% 44 19 (C) 5.9 50% 68% 17 12 (c) 1.6 19 (6) 0.72 33% 39% 6.8 34 > 10 36 5 (a) 0.03 28% 10.4 12 9.6 12 (d) 0.39 31% 61% θ 1 > 10 51 13 1.3 61% 74% 3.9 28 > 10 69 15 15 I6 (a) -0.08 28% Nl 65% Nl Nl 4.5 112 8 T 6 (a) 0.74 33% 67% 8.5 50 3.5 * 69 5 (b) 0.9 78% 14 3.7 33 8.5 16 (b) 0.34 22% 73% 4.7 140 > 10 50 16 (c) 1.1 1001000 > 10 16 (6) 0.43 33% 90% 11 > 10 16 (e) 1.3 8% 59% 4.9 106 > 10 40 6 (b) 0.15 81% 95% 8 60 4 128 16 (f) 2.8 > 30 > 10 19 (e) 20 > 300 30 (a) 1.7 45% 94% 1.6 22 5.7 64 19 (1) 0.18 52% 58% 2.3 16 3.9 98 46 3.5 30 (b) 2.2 90 19 (q) 0.86 19% 59% 18 1920 90 30 (c) 0.83 44% 82% 2.5 21 54 19 (hl 600 7.9 44 9.6 > 700 38 (a) 0.22 77% 74% 4,5 20 10.7 72 45 (b) 99% 86% 79% 1.9 11.5 4.4 97 45 (a) 0,062J - - 3.1 ca; 15 3.5 97 i9í! L > 300 daa. 0,046 79% 53 65 0.8 8 5.5 92 38 (b) 72% 79 19Í1L 0.33 23% 44% 2.2 50 > 10 66 42 (b) 0.35 75% 27% 2.1 29 2.1 81 19 [£ 100% 37% 41% 2.6 28 4 58 33 [b}. 0.66 76% 63% 77% 0.8 11.5 15 45 26 LL θιθ 3.2 19i! L 0.72 36% 88% £ 6 100

376

19 (m) 0.68 35% 23% 94 > 10 61 33 {a) 3 _r 8 42% 9% 0 56 2% 7% £ 0 2Z. > 10 29 19 (n) 0.54 26% 48% 3.4 23 2.9 33 (c) 0.28 26% 76% 6.6 > 10 16 33 (d) 0.14 55% 24 > 300 8 22 40 (a) 17.9 41 (aa) 0.11 % 49 37% 1 5.2 > 10 100 41 (b) 0.26 24% 31% 2 9.8 > 10 80 m 42 (e) 1.1 95 42 (d) 1.7 44 > 10 43 2.6 56% 24 2 19 (0) 89% 20 41 (c) 0.22 83% 36% 77% 0 ^ 5.3 68 41 (d) 0,093 O, ⁹ 41 (a) 0.03 94% 50% 0 20 0 6% 0.48 4.4 > 10 96 19 (p) 1.5 41 (e) 0.22 21% 31% 0.15 5.6. 6.1 22 41 (f) 0.11 84% 65% 92% 0.45 20 59 41 (g) θ 1 36% 95% 0.9 > 10 52 30 (d) 0.37 3.8 30 (e) 0.37 62% 92% 29 33 (e) 1.7 70% 2% 68% 0.46 5 > 10 54 W - -TR- -31- 41 (h) 90% 30% 2 25 8 47 0.25 50% 88% 31 (a) 0.29 77% * 95% 0.7 10 58 41 (1) 0.04 38% * 76% 0.25 3.3 48 35 (u) 79% 2.6 27 32 (a) <0.1 86% * 96% 0.16 4.5 2 41 (a) 2.95 20% % 49 48 41 (1) 0.24 63% * 66% 386 41 (m) 0.75 40% 67% 23 0 41 (n) .0,2. · 66% 87% _ _ - - 28- 70 31 (b) <0.1 66% 97% 5.6 2 41 (0) 0.05 77% 74% 10 94 31 (C) <0.1 81% 98% H _f 4 87 35 (gg) 23% > 100 33 (g) 15% 34 97% 78% 95% 15 28 50 35 (A) 72% 11% 59% 22 26

377

35 (w) 59% 35 35 (x) 75% 2 37 35 (a) 76% 12% 59% 2.1 33 35 (b) % 49 12% 59% 35 35 (C) 76% 11% 42% 6.3 - 17 41 (p) 0.06 % 49 0 90 6% 3% 0.27 2.6 > 10 62 42 (C) 95% 1 to 3 41 (dd) 98% 50% 69% 5.8 7 41 (bb) 99% 7E% 88% 1to3 110 35 (s) 99% 29% 82% 1 to 3 7 35 (d) 76% > 100 31 (d) 96% 52% 0 14 5% 9% ca. 13 110 41 (q) 100% 53% 91% 2.7 35 (e) 99% 56% 69% 4.8 > 10 34 35 (f) 100% 8 15 35 (g) 100% ca. 15 53 35 (h) 100% 3.6 9 35 (1) 100% 4.7 35 (j) 99% 1.5 5 35 (k) 85% 6% 0 34% 8% 7% 2.2 > 10 14 41 (ee) 0 _; 13 13% 0 94% 0 2% 0.24 4.3. 2.7 M- 47 3 b (z) 95% -2- 35 (aa) 99% 5 15 41 (r) 100% 55% 0 92% 0 5% 11 83 41 (CC) 97% 41% 95% > 100 35 (l) 90% 12 35 (cc) 89% 15% 0 74% 5% 6% 0.05 1.6 31 35 (ee) 82% 3 13 35 (ff) 0 11 25% 75% 5.8 31 35 (d) 0.6 17% 0 75 .7% 8% 0.18 -2,9- > 10 26 35 (bb) 87% 4.1 8 32 (b) 0.08 70% 95% 21 > 10 35 (hh) 100% 34% 73% 7 35 (m) 0.04 61% 82% 35 - "(a) 0.37 13% 0 14 0 0 8.8 55 39 (a) 53% 1.4 ca. 50 70 35 (n) 0.83 58% 23% 92 4% 10% 0.11 11 5.1 47 41 (a) 0.23 53% 86%

378

35 (0) 39% 17% 44% > 100 41 (1) 0.06 51% 0 85% 1% 2% 3.8 87 32 (c) 0.27 52% 96% > 30 36 (b) 85% 22% 43% > 30 37 (d) 26% 10% 38% > 100 37 (c) 83% 12% 39% • 12 21 37 (b) 48% 8% 36% 30- 100 59 (a) 41 (u) 0.08 54% 74% ⁷ ? ⁹ 41 (hh) 98% 13% 74% 3.9 72 36 (c) 89% • 28% 60% > 30 36 (a) 87% 19% 38% 19 58 35 (p) 62% 5% 11% > 30 35 (q) 92% 42% 51% 18 40 (b) 89% 32% 92% 41 (ff) 98% 15% 12 5.6 68 37 (a) 57% 6% 35% 15 21 41 (A) 68% - * 52% 68% 12 41 (11) 57% 18% 11 13 85 35 (r) 0.11 16% 20 0.36 2.3 > 10 51 35 (a) 60% ♦ 18% 64% of 4.6 16 35 (t) 59% • 12% 63% 4 7 41 ( ») 95% 14% 91% 23 41 (w) 97% % 49 67% ca. 10 41 (X) 98% 66% 3.4 4.6 100 41 (mm) 93% 6% 46% 1.3 14.4 94 41 (JJ) 87% 19% 81% 21 4i (s) 98% 61% 86% 30 '100 0.02 43% . - .. ~ 62% - - 6.2 8.6 49 40 (c) 24% 28% 59% 41 (99) 84% 27% 3.5 9.5 50 41 (nn) 57% 7% 91% > 100 41 ') 98% 16% 41% 7.7 48 (b) 97% 6% 77% ca. 8 41 (2) 100% 54% 74% 7.5 41 (kk) 100% 26% 97% 16 63 39 (b) 2.8 10% 50% > 10 67 31 (f) 97% 62% 99% > 10

379

59 (b) 49 (a) 00:04 11% 79 ca. 4 8 _f 4 59 (c) 49 (b) 98% 9% 80% ca. 10 56 5% 35 (11) 44% 59 (d) 57 100% 30% 89% 59 (e) 58 98% 19% 98%

Table 2

PtíW. no. CDK2 * CDK4 * CH Kí * FLVK-P * lcie FGF * HCT-116 IC50 24 (a) 0,017 0.0051 0,028 0.0983 67% 72% 0.23 24 (b) 0,021 0.0032 0.02 0.0331 96% 88% 0.37 24 (c) 0.0034 0.0015 0,044 0.0142 93% 89% 0.44 24 (m) 17% 16% Nl © 20 μΜ 24 (1) 0,086 0,071 62% © 20 μΜ 3.8 -24 (dy -0 ^ 83 ~ 0,017- 0,056 0ýl25 · -66% " 0, O23 - 24 (e) 0.03 0.0044 75% 52% 0.15 24 (f) 0.0072 0.0074 97% 89% 1.5 24 (g) 0.13 0,029 1.67 0,194 > 5 24 (0) 0,029 0.2 2.2 24 (h) 0,054 0,053 3.6 24 (1) 0,055 0,013 1.7 240) . ·. 2.1. .. 0.32. .... _ _ • .... - 24 (a) 0,056 0.0072 81% 89% 0.16 0.2 25 {a) 0.08 0.02 % 49 44% 62% 0,051 24 (n) 0,035 0,019 1.5 25 (b) 0,112 0,048 B3% 87% 87% 2.1 25 (C) 0,233 0.0155 90% 96% 0.25 25 (d) 0.16 0,098 87% 60% 80% 25 (e) 0,477 0,181 16% 13% 26% 25 (f) 0.39 1 Nl 58% 56% 0,098 25 (g) 0.08 0,021 21% 76% 82% 2 25 (h) 0.17 0,024 86% 87 91 0.32

at

NI

380

25 (1) 0,021 0.02 > 5 24 (p) 0,089 0,092 0.44 25 (j) 0,079 0,016 70 0.0083

* values represent Ki (μΜ) or% inhibition of compound concentration of 1 μΜ, unless otherwise indicated indicates insignificant inhibition

Table 3

Example # CHK-I ' CDK1 * CDK2 * CDK4 * FLVK * 28 (d) 0,018 93% 66% 87% 27 (j) 15% 50 50µM 27 (a) what CO • x o NI © 1 μΜ NI © 100 μΜ 28% 5 5 μΜ 71% 27 (b) 28% 50 50 μΜ 28 (a) 0,108 77% 75% 79% 84% 27 (c) 11% 5 5 μΜ 28 (b) 0.0143 97% 98% 96% 27 (d) .14% © 10 μΜ -27 (e). . . 0,757. - - 34% 27 (l) 0,227 85% 73% 92% 27 (f) 0.35 0,223 3.3 0.78 % 49 27 (h) 0,311 84% 27 (a) 24 28 (c) 1.14 34% 27 (g) 0.85 52 (b) 0.08 0,041 0,241 0,117 94%

381

55 10 52 (a) 0,263 39% 60% 53 (a) 0,301 24 13% 5 5 μΜ 28% 5 5 μΜ 29 (b) 0,138 0.9 3 3.9 29 (a) Nl © 25μΜ 29 (c) ⁿ 0,174 56% 2.2 2 29 (d) 10 29 (e) 0,074 0,593 1.4 2 33% 29 (f) 0,418 51 0,087 0,146 84% 79% 29 (r) 9,072 0,066 1.3 1.1 29 (g) 0,068 0.39 1.4 1.1. 29 (h) 0.14 1.3 3 2.2 54 (d) 0.68 Ni Q 1μΜ 54 (b) 3.1 29 (1) 0,104 . 26% 3.1 5 --53 (d) __ Nl Q 100 μΜ 54 (e) 0,342 Ni Q 1μΜ 54 (a) 0,896 1% 53 (c) 1.1 290) 0,533 31% 29 (q) 11 11% 29 (p) 0,232 6% . 53 (b). 4,4- ....... - - - - 29 (a) 1.3 54 (f) 2.9 54 (c) 0,125 Nl {54 g) 0,195 3% 29 (0) 46 53 (e) 0,886 13% 29 (1) 1.4 7% 29 (n) · 16

382

29 (m) 1 54% 53 (f) 7.3 54 (h) 1 29 (a) 11 54 ') 0,424 54 (1) 0,461 29 (t) 0,072 29 (u) 0.151. 53 (g) 1.5 54 (1) 0.99 54 (a)

* values represent Ki (μΜ) or% inhibition at a compound concentration of 1 μΜ unless otherwise noted. NI indicates insignificant inhibition

Library example

X, in Table I

Three library building blocks ("amine templates") 6- (3-aminophenoxy) -3-E-styryl-1H-indazole (Y = 0), 6- (3-aminobenzoyl) 3-E-styryl-1H-indazole (Y = CO) and 6- (3-aminophenyl) amino-3-Eryryl-1H-indazole (Y = NH) were prepared as described in Example 7, Example 18 and Example 46, respectively. 0.1M acid, amine template, o- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium hexafluorophosphate and triethylamine solutions were prepared separately in anhydrous DMF. To each tube in a group of 8x11 culture tubes (10x75 mm) was added 105 μύ (0.0105 mmol) of a different acid. To this was added 100 μΐ (0.01 mmol) of the amine solution, 105 μΐ (0.0105

383 mmol) of triethylamine followed by 105 μΐ (0.0105 mmol) of O- (7-azabenzotriazole-l-yl) -N, N, ^N ', N'-tetramethyluronium hexafluorophosphate. The reactions were stirred in a heated block at 50 ° C for 3 hours. The reaction mixtures were transferred to 1 ml 96 well plates using a multipipette. Solvents were removed using a SpeedVac ™ and the crude reaction mixtures were redissolved in DMSO to give a final theoretical concentration of 10 mM.

The compounds in the table were tested for inhibition of HUVEC proliferation at a nominal concentration of 10 nM and the results are shown in Table I below, calculated from the formula:

% inhibition = (control - treated) / (control - fasting) x

100

Under these test conditions, > 50% inhibition is considered significant.

Library table

R * y = Y = o y =

CO NH

CH, 134 127 135 • Φ, φ y 124 145 118 H, C ^ H, 128 94 115

R * Y = Y = O Y =

CO NH

134 138 112 υγ. 3 56 111 H, _C ^ y y 30 ' 91 109 about 101 157 105

384

hc / y ' _n -n H 113 150 86 C _H , H, C ^ cA ^X ' 72 . θ7 85 Xi ^ Os 128 92 81 CC. Η, Ο'θ 113 30 ' 80 HJC = CH, (T 51 35 79 ^H A .y *. 125 122 78 URCR ^ F pXjLx *? 87 80 77 ^H Ί ^Hh O ^{x X} H, C 26 52 76 CH, CH, 99 52 75

385

ζ. ï 54 85 71 C F 80 91 64 71 52 60 NQL ^ x, 21 76 43 ςύ. F 81 93 40 H + jQ ^ X, S7 86 34 fH, h, c ' ⁿ Y ^Sv ' ^x 'S 25 70 32 CX ^ * ¹ 2 52 30 <? H ₃ I_ | Q'n ^^ XX ^ X, 24 96 30 35 64 30

37 48 30 "XT- ' 57 70 29 CH, CT '' 52 42 27 Η, θγ-γΧ, CH, OH 47 69 25 ^H 3 ^C X H, CH 2 CH, 51 71 25 35 57 24 CH, and 18 51 23 ΟγΧ. 0 45 57 23 rv H, 19 22 20 H _v 32 32 20

386

r HJC 10 24 20 _ν σ 'CH, 33 42 13 HS y *? H, 24 45 19 0 3 36 13 Y 0 14 90 12 -13 18 17 OY ' -37 25 11 H ΟγΝγΧ, ^H Y. 0 -36 -6 17 CH, O 81 64 11 -T? 1 -2 25 17 «3% 47 17 10 H, C ^ - ---- ? ^H 'X' .cV ^ ^h y 3 24 16 H, C OH 27 30 10 H ₃ C H.cJy '· H, 5 23 7 r 5 25 16 H _v ΐΉ H 21 40 7 & ^H -1 30 15 H.c-fr 'O' N 50 112 6

387

96 134 6 42 13 6 HO \ ^ OH -20 25 6 44 82 5 ? H 33 32 3 ^H X ^ x 0 4 2 n ^ hOr * ¹ 20 43 0 c, cT 8 23 0 Í ^H 'Η ₁ <Γ ⁵⁶ Ν' ° 'γ' ^Χ 'CH, 28 80 -1 _ 0 ^ ⁰ ¾ - -σ ^χ · 10 19 -2 <r 12 40 -3

9y ^'ch A _CH 3 46 -3 39 -4 O 2 ^CH 3 37 20 -5 -11 52 -7 xr -HO- -59- -7-  - 0 27 48 -8 _____ .. -CH 2 64 83 -8 yä CHjC 35 42 -9 o x 27 52 -9

388

31 20 -17 56 17 -17 V ' ⁰ -20 18 -18 OH 64 38 -20

Example of library II (a) when Y = S in formula I

6- [2- (pentafluorophenoxycarbonyl) phenylsulfanyl] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole (Y = S) was prepared as described in Example 35 (a). 1.5 µM solutions of 261 amines and 0, 1393 µΐ (1.0 µπιοί) EtaN, dissolved in 15 µΐ DMF, were dispensed into wells of a 96 well plate. In cases where the amine was used as the hydrochloride, an additional 0.4179 μΐ was added

389 (3.0 μπιοί) Et ₃ N to release the free base. Each well was treated with a solution of 0.5395 mg (1.0 pmol) of pentafluorophenyl ester (dissolved in 30 μΐ DMF) and then the plate was shaken for 24 hours at room temperature. The crude reaction mixtures were concentrated using a GeneVac ™ and then undiluted DMSO to a final concentration of 10 mM.

(b) when Y = NH in Formula I

R nHFC

DMF.EfcN. HATU, 24h

2.0 μπ of solutions of 263 amines and 0.4181 μΐ (3.0 μπιοί) of Et ₃ N were dissolved in 20 μΐ of DMF and dispensed into wells of a 96 well plate. In cases where the amine was used as the hydrochloride, an additional 0.5575 μΐ (4.0 μπιοί) Et ₃ N was added to liberate the free base. Each well was treated with a solution of 0.47 mg (0.75 μπιοί) of 6- [2-carboxyphenylamino] -3-E- [2- (pyridin-2-yl) ethenyl] -1H-indazole dissolved in 20 μΐ of DMF, followed by 0 570 mg (1.5 μπιοί) of HATU solution dissolved in 10 μΐ DMF, and then the plate was shaken for 72 hours at room temperature. blends were. concentrated using a GeneVac ™ instrument and then diluted with DMSO to a final concentration of 10 mM.

Compounds in the table were tested for inhibition of HUVEC proliferation at a nominal concentration of 0.5 and 2 nM for Y = S and the results are shown below as calculated from the formula:% inhibition = (control-treated) / (control-fasting) x 100

390

Under these test conditions, > 50% inhibition is considered significant.

Library Table II

R ' 0.5 nM 2 nM 19 89 38 2 & 37 16 / 39 15 35 10 P ” ¹ ý x ' 32 31 5 14 x? 14 55 23 44

Z ⁵ XÍ 25 35 H »C ~» Q x / 30 23 5 19 70 105 Λ x ' 25 15 q P 44 19 £ ^N 'ch, H- ^ch >X,' CH, 38 5 OH P 23 6

391

% -ΟΗ 4 20 O-CH 21 60 u. 34 61 -O Xí 23 23 r * o 26 37 .. .. x ( A 2 6 32 24 9 ° _R P = ° χ / OH 32 6 amino-y ^ χΛ OH 48 β y ' 45 88 p xf ^NH * 17 4

392

η X Ο v 18 32 6 43 30 78 34 58 Λ " χ / 0 « 22 20 Η C P ”y 19 28 _. PH. < ^Ν · Λ CH, χ { 6 1 JrCH. χ. ' 20 10 CH, r + ^ and X {CH, 31 3 IN H, 32 10

/ -CH, r-N-'-CH, 31 -1 Λ 6 4 Λ 4 29 Λ 23 61 OH 18 24 b 21 15 - H-ch, b -1 26 [^ N ^ C-N] x ( -6 0 _x Az ^ o: VJ Λ 1 - í & 5 'O · - · ť 23 17

393

394

FROM A 18 22 H-X1 9 30 H ° L X, 7 25 Η, σ ^ χ, 16 17 ϊξσ ^ χ, 13 31 95 106 59 97 30 86 22 43 Λ 33 64 28 29 x Η, σ '^ χ, 31 20 O ^ x, 42 80 <R * 25 53 CH. 65 110

395

29 58 52 107 CH. 31 36 ° yS CH, 4 10 8 23 "-X 13 20 33 18 cx 20 25 Η, (/ °> 62 99 / SL 6 16 Ck * 17 13 / = ^ 19 22 / Ί 39 18 44 5 43 96

396

28 14 in, -6 41 α 12 76 R 33 94 α 27 17 44 28 r- r 55 50 21 90 and, 12 53 • U, 21 64 cr * 35 63 «.OyCH. * <A <. 21 -5

r 1 65 28 103 «» 51 105 44 97 Λ 44 40 », <<, 04, HO ^ X 47 -4 Η, χ ^ ίΤθγ, ^ CH, 47 89 IO PQ - ch, with Rís --- -UV 44 100 a ^ x, 35 69 16 2 rr ^s 32 92 92 103

397

9 1 The 56 96 CH. ï 26 2 A ^ ⁰ '· 39 13 • ^ ys 0 19 5 HC < ^{X X} - ^{X X} X ₁ 24 31 35 106 to 15 36 a- 69 59 Ύ \ -11 42 16 42

15 95 20 92 19 -1 X 31 30 -1 14 9 34 'Ύ ^ 6 44 1 52 h ^ ch * A. CH, 18 -2 X 9 -9 ABOUT 40 94

398

cu. 38 68 25 40 34 99 d ' 30 94 5 ¢ ^ 24 99 19 101 20 92 Oh, 15 99 and ^% 16 37 axis 17 - 23 CU 70 111

0 60 99 6 ~ ' 75 114 81 95 OO'x. 24 86 CH, -3 64 oys 26 71 14 60 - v yk, 51 108 h 8 37 feature ^Vh S CH, 15 23 .Λ-Λ 20 32 --- 35 63

399

28 47 26 16 axis 18 11 y./- ^p 13 7 28 69 18 43 ΗΓχχ'Ο ^ γΖ'Χ ™ XI ' 11 47 19 86 - - -. - y 26 83 cr ~ · ' 50 111

400

α, νΑ ₀ 21 39 10 29 h 'V'-VS 16 2 22 36 σ ' 18 29 25 25 The ií ^ ⁰ ^ 27 80 Λ H, c ^{, z} ' ^x cr ^x ' - ^Z ' ^x ^ 30 70 10 23 0-Λ 50 40 51 67 23 51

401

402

Ο, am solutions of amines, triethylamine and 4-dimethylaminopyridine were prepared separately in anhydrous DMF and transferred to a safety box. 0.1M solution of 6- [2- (carboxy) phenylsulfanyl] 3-E- [2- (pyridin-2-yl) ethenyl] -4-indazole, Example 33 (g), tetrabutylammonium salt and o- (7-azabenzotriazole) (1-yl) -Ν, Ν, Ν ', N'-methylmethyluronium hexafluorophosphate were prepared in a safety box. To each tube in a group of 8x11 culture tubes (10x75 mm) in a safety box was added 100 μΐ (0.01 mmol) of different amine solutions, followed by the addition of 100 μΐ (0.01 mmol) of tetrabutylammonium-2- {3 - [(E (2-) - (2-pyridinyl) ethylyl] -1H-indazol-6-yl} sulfanyl) benzoate, 100 μΐ (0.01 mmol) triethylamine solution, 100 μΐ (0.01 mmol) 4-dimethylaminopyridine solution and 100 μΐ ( 0.01 mmol) o- (7-azabenzotriazol-1-yl) N, N, N ', N'-tetramethyluronium hexafluorophosphate. The reactions were stirred in a heated block at 50 ° C for 1 hour. Reactions of the reaction mixture were transferred to 1 ml 96 well plate using a multipipette. Solvents were removed using a SpeedVac ™ and the crude reaction mixtures were redissolved in DMSO to give a final theoretical concentration of 10 mM.

403

The compounds in the table were tested for inhibition of HUVEC proliferation at a nominal concentration of 0.5 nM and the results are shown in Table III below, as calculated from the formula:

% inhibition = (control - treated) / (control - fasting) x 100

Under these test conditions, > 30% inhibition is considered significant.

Library Table III

R% inhibition

1 ----------------- 1 -1 ή · -17 HO H ay 4 'ύ 17 o x 6

R% inhibition

22 ... ___X, -19 ° CH _and J F 9 Ό ’ CH, 2 5

404

405

406

407

408

409

410

7 ^Η · ° ^Λσ υ -4 X ΟΗ 4 fi γ ΟΗ 7 - 0 —-- ο ^ 'Χ » 7. < ^ν Λ 18 f Δ, 11 Ο $ 0 -31

411

"about CH, -22 "And -5 -1 x, H, C - CH, T ..... £ ............. -7 4 -22 N X = CH, -3 ^Μα ^ ^0Η · 11

x. 4 “Φ OH 20 15 ° 'O' ° -45 -37 f ¹ H _with C.UyCH ₃ -20 ^h - ⁰ '^ ^ch · -4 f. H, C — 4 — CH, ^H in ^H 3 ^{C <} CH, 0

412

H, C — τ — CH, Η ₃ σ -29 [ f. ClxJx ^ CH, V CH, -26 3 '' ô ' ¹ ' 8 - You - 12 f. H, C-4-chlorophenyl, ^ο Λ ο HJC-j-CH, CH, 6 H, ^'Person | ^ J ^XO CH -57 f ’H, C - (- CH, -25

-41 s · ^h j ^c 'N ^ N 6 -21 Ä Η, βγ-Ν h, c -28 L, H, C -20 L z -20 ï 3 ° ΰ . 11

413

Λ CH, -28 4 OH -10 * Λ -13 13 -7 -13 > OH T CH, -45

414

415

, ľ. HO J OH HO 14 y. / HO J CH. HO ’ 61 £ HO ^ X .'CH, ηο ' ^ν χη. 9 joo 1 ΟηΛ 1 at 4 CQ X, 1 Cl 8

_C X) -15 Cl -12 OH 52 O ^ CH, 19 -------- 0 o x 13 ° -ô -7 fYV * ¹ OH -26

416

A F-F F 5 x 1 í ΐί * Ί F-τ-F -3 _x -13 about x «3 ° CH, -1

417

Ť ó CH, -1 s 16 X. 4 Φ -23 CH, -20 s -15

418

D- -3 Ah ď -11 n -NH 22 c / 9 . -5 x, ^Η 'Ύ CH ^ OH -19 -6

-12 X, ^ΗΟ γΊ Ó -1 N-NH -7 f ' HO, J γΊι 2 £ HO ^ J -34 UAO -13 h ₅ o. ₀ XX> CH, 13

419

Cl 48 36 T -8 > ^ S υ and and -11 H, C. ₀ X ^. ° * CH _and 1 -4 Y Y Η, Ο * ⁰ 10

420

421

CH, -6 CH, 13 Ť φ CH, -1 -------------------------------------------------- --------------- ---------------------------------- 1 ------------------------- I i ________ -11 Y 11 I U. 7 15

-8 XAjjOO CH, 1 J, Y F 3 J 'X 9 n X O ý I -i -------------------------- 2 Y 6 d> 15

422

about N 6 0 J » 2 CH, -1 í f · HAoAJ} 3 18 Oó. -17 P -8 p 3

423

0 H ₃ C ' ^N ' CH 3 18 7 J -6 s (Γί ------------- O ^ NH - 2 SRS 3 OH 14

424

Μ -7 Η,% ΧΡ ° 'CH, -3 4 PART -......... CH, 8 H, C-° «H · 10 PART 7

DJ H, -9 46 xi 2 23 5 »H _and * 1 CC, 11 CH, -10 H, C NH 1 O -4

425

/ HO -2 A 5 s -13 Λ O κ, σ -9 ° = <θΗ, CH -2 Λ ABOUT H.C CH, -6 S ^ N H WITH H, C 17

426

ά HaC 19 x, Φ OH 18 about H? O HjCr -24 ''-ABOUT- 0 and "about -6 Ä 3

Λ N ^ N η, ο ^^ Ύ ' ¹ CH, -20 * In r ° CH, -16 b C CH, -19 1 «M · ABOUT 3 r / h ₃ c ^A ^ ⁿ · 6 PART 18 what

427

JS H CKs HO k. ^ OH -18 X 'H, c' ° -9 fl 04 2 y 14 -10 Ť Ô H _S C ' ^Š -7 X 4

CH, 11 α H, C ^H 11 Λ CH, 8 H, C £ -CH CH, 23 ktzXjU * Η, Ο ^ 'Χ, IN x <Sh. -20 J 0

428

7 57 Cl 24 x. (Ý · 1 f. ^{H, C CH} xj ......... CH ---- -10 -8 -2 5

429

Table 4

0 ^N \ x R jf in R CHK-1 © 20μΜ Cà 30.6 28.3 Ηθχ ^ \> ς 22 _? 5 QT 21.7 D 40 ΟγΌ NH, 27.8 20.2. 57.7 35.5

430

> CR 24.2  31.1 13.7 y 23.9 48.6 19.5 32.3 0¼ 24.9 ΝΗ. ° Χι 25.8 ΧΓ 94.9 <xr 38.7 ν .72

431

α 21.1 αΤ 31.4 πο-Ο. 28.3 CH, 28, δ Ο 28.1 25.7 ηο'Ί'Ο · 23.9 α 36.3 α 45.4 32.7 24.7

432

52.7 '9γ ^ς Ν ^ Ν 38.6 23.6 39.8 28.1 33 γ 52.4 38.6 32.3 42.9 24.1 Π η ^ ότ 31.6

433

Table 5

% inhibition @ 1 μΜ Example C. Tie2-P FAK 41 (a) 50 5 41 (ee) 41 7 41 (p) 49 9 41 (r) 56 5 41 (t) 51 9 48 (a) 52 11 31 (d) 46 6 33 (a) 35 12 35 (k) 55 7 35 (d) 48 4 35 (n) 82 1 35 (cc) 47 7

434

l (a) * 95 * 69 3 NI * * 26 8 (a) * 55 3 * 2 (d) * 90 NI * 8 (c) * 31 * 15 9 (b) * 88 NI * 10 * 20 NI * 17 50 -. - - ’- 4 (a) 69 11 40 4 (b) 29 2 (c) - NI 22 (a) 8 23 5

435

22 (b) NI 21 27 12 (a) NI 19 (a) 18 19 (c) NI 12 (c) 17 19 (d) 15 5 (a) 44 -i € (a) --- 1Ό ----- 16 (b) 52 24 (a) * 91 24 (10 * 92 24 (c) 94 30 (a) 19

436

8 (d) 10

* Compound tested at 10 μΜ

Bold values refer to spectrophotometric test results, bold values were obtained in DELFIA

Determination of inhibitor concentration in mouse plasma following intraperitoneal and oral dosing

The dosing solution consisted of an inhibitor dissolved in one of the following vehicles: either a 30% or 60% aqueous solution of polypropylene glycol with a molar equivalent of HCl in water or 0.5% carboxymethylcellulose in water. The final concentration was normally 5 mg / ml with a dosing volume of 5 or 10 ml / kg. Taconic female mice (Germantown, NY) were dosed as a function of compound weight to body weight, usually 50 or 25 mg / kg. Blood donations were taken from the ocular vein at 0.5, 1, 4 hours with a final time point of 7 hours when blood was drawn by intracardiac puncture. Blood was centrifuged to collect plasma, which was then stored at 80 ° C until analysis. Samples were prepared for analysis using an internal standard and sodium hydroxide. After vortexing, ethyl acetate was added and stirred for 15-20 minutes at room temperature. After centrifugation, the resulting organic layer was evaporated and then reconstituted in acetonitrile and buffer. The samples were then analyzed by HPLC or LC-MS.

Compound levels were quantified using a standard curve of known compound concentration in mouse plasma. levels

437 compounds were plotted as a function of time and analyzed by determining the area under the concentration curve (AUC ng * hr / ml), maximum concentration (Cmax ng / ml), minimum concentration (Cmin or 7 hours ng / ml) and terminal half-life (Tl / 2 hours). The results are shown in the table

6th

Table 6

Example # process Dose mg / kg ADClast (ng * hr / ml) Cmax (ng / ml) Cmin (7 hrs.) (Ng / ml) Tva 8 (h) Vehicle PEG400: H ₂ 0. pH 2.3 1 (a) IP 50 691 283 2.4 30/70 19 (b) AFTER 50 ON THE 30 • 60:40 19Q) IP 25 23205 5764 456 1.6 60:40 19 0) AFTER 50 5889 1937 63 1.2 60:40 19 k IP 25 426 149 15 2.2 60:40 19 (k). AFTER 50 19 8 4 2.2 60:40 31 (al IP 25 47538 13018 1906 2.4 30/70 31 (a) AFTER 50 40863 14499 834 1.6 30/70 31 b IP 25 > 7037 > 2,000 177 í 7 30/70 31 (b). AFTER 50 2071 1100 15 1.0 30/70 31 (d) IP 25 237784 64184 15073 5.3 30/70 31 (d) AFTER 10 49120 9740 2022 3.1 30/70 31 (d) AFTER 25th 203860 50810 3801 1.9 30/70 31 (d) AFTER 50 430683 76915 42478 38.3 30/70 31 (e) AFTER 25 > 30339 > 5000 2952 13.1 30/70 AFTER 25 > 244545 > 50000 9521 2.6 30/70 32 (a) IP 25 > 20554 > 4000 1273 3.7 30/70 32 (a) AFTER 50 4190 1746 40 1.1 30/70 32 b AFTER 25 .490 179- -48- -íM- -3017G-- 32 (C) AFTER 25 388 161 10 2.4 30/70 33 (a) IP 25 13813 13794 54 1.1 3Q: 70. 33 (a) AFTER 100 3556 90 0.5% CMC 33 (a) AFTER 25 721 66 0.5% CMC 33 (a) AFTER 50 19067 23562 25 0.8 30/70 33 (b) IP 25 11245 1990 902 3.0 60:40 33 (b) AFTER 50 3925 1496 76 3.0 60:40 33 (0, IP 25 697 505 7 1.2 30/70 33 (c) AFTER 50 183 94 5 3.0 30/70 33 (dl IP 25 5080 1738 113 1.6 60:40 33 (d) AFTER 50 4744 1614 8 0.9 60:40 33 (e) ÍP 25 14323 9938 94 1.0 30/70 33 (e) AFTER 50 13290 9967 12 0.7 30/70 33 (t) IP 25 1887 1699 6 2.4 30/70

438

33 (f) AFTER 50 1436 1186 3 AL. 30/70 35 (a) IP 25 2032 2138 24 1A. 30/70 35 (a) AFTER 50 2445 1780 • 10 0.9 30/70 35 (aa) AFTER 25 · 4036 4168 106 2.1 30/70 35 b IP 25 2840 1509 12 0.8 30/70 35 b AFTER 50 4048 5595 13 about 00 30/70 35 (c) IP 25 9408 1976 465 AA 30/70 35 (c) . AFTER 50 4744 909 321 AA 30/70 35 (cc) IP 25 2223 3183 6 AL 30/70 35 (cc) AFTER 50 1718 1439 5 0.9 30/70 35 (dd) IP 25 > 23046 > 4000 1364 AL 30/70 35 (dd) AFTER 25 1360 444 58 AA 0.5% CMC 35 (dd) AFTER 25 > 6521 > 4000 114 M 30/70 35 e IP 25 2409 1272 65 1.8 30/70 35 e AFTER 50 1503 1043 6 0.9 30/70 35 (ee) IP 25 546 579 2 1.5 30/70 35 (ee) AFTER 25 157 77 9 14.6 30/70 35 (f) IP 25 397 131 25 3.8 30/70 35 (f) AFTER 50 358 93 27 3.6 30/70 35 (ff) IP 25 > 6301 > 4000 72 AL 30/70 35 (ff) AFTER 25 Bologna  blq. Bologna 30/70 35 (g) AFTER 25 231 61 28 16.1 30/70 35 (h) IP 25 59 46 1 1.5 30/70 35 (h) AFTER 50 26 7 2 w 30/70 35 {HHL AFTER 9 *; 9Q9 991 C -1-7- --- --- £ íM-- 35 0) AFTER 25 30/70 35 (j) IP 25 9531 8606 52 1.3 30/70 35 G). AFTER 50 1328 2176 5 4.5 30/70 35 k IP 25 2640 2189 35 1 _f 4 30/70 35 k AFTER 50 5529 4524 33 1.4 30/70 35 (m) IP 25 226 58 17 4.0 30/70 35 (m) AFTER 25 10 7 0 « 30/70 35 (n) AFTER 25 4818 3545 55 1.4 30/70 -354) AFTER 25 683 486 3 ‘’ 1.0 30/70 35 (p) AFTER 25 1435 1958 5 1.3 30/70 35 (r) AFTER 25 4261 2601 67 1.3 30/70 35 (s) AFTER 25 7425 3371 86 2.2 30/70 35 (t) AFTER 25 3199 2801 41 1.1 30/70 35 (u) AFTER 25 30/70 35 (A) IP 25 4865 2215 16 0.9 30/70 35 (v) AFTER 50 > 2946 > 2,000 26 1.0 30/70 35 (x) IP 25 951 781 48 3.2 30/70 35 (x) AFTER 50 3516 2313 16 0.9 30/70 • 35 (s) IP 25 159 135 2 1.2 30/70 35 (s) AFTER 50 58 45 1 .AA 30/70

439

35 (z) IP 25 837 556 22 1A. 30/70 35 (z) AFTER 50 100Ϊ 806 14 ± 6th 30/70 36 (a) AFTER 25 605 445 17 30/70 37 (a) AFTER 25 30/70 37 (0 AFTER 25 2419 2338 9 ϋ 30/70 39 (a) AFTER 25 > 14848 > 4000 219 1.4 30/70 39 (b) AFTER 25 > 30972 > 5000 3148 11.8 30/70 4 (a) AFTER 50 ON THE 50 ON THE 60:40 41 (a) IP 25 92823 32202 3856 2.9 30/70 41 (a) AFTER 50 48998 18433 2462 30/70 41 (aa) IP 25 6659 2427 124 2.1 60:40 41 (aa) AFTER 50 289 259 5 0.9 60:40 41 (b) IP 25 > 5868 > 1000 412 4.7 60:40 41 (bL AFTER 50 759 532 6 1.1 60:40 41 (bb) AFTER 50 2178 596 75 2.0 30/70 41 (0 'P 25 3397 2068 57 1.7 60:40 41 (0 AFTER 50 3182 1296 104 -2Λ 60:40 41 d IP 25 10324 2787 573 2JB 60:40 41 (0 AFTER 50 7072 2954 150 1.5 60:40 41 (dd) AFTER 25 654 542 1 0.8 30/70 41 (eĹ IP 25 4900 1154 301 1.6 60:40 41 CeL AFTER 50 302 ' 113 7 1.6 60:40 41 (ee) IP 25 > 28434 > 5000 1670 4.0 30/70 41 (ee) AFTER 50 > 25294 > 5000 1214 3.4 30/70 41 (ff) AFTER 25 9176 - -2784- -410- --30 ^ 0-- 41 (gl IP 25 1925 1583 0 0.3 60:40 41 (gl AFTER 50 508 842 1 0.7 60:40 41 (gg) AFTER 25 2692 2079 29 1.1 30/70 41 (hl IP 25 26911 16005 300 1.2 30/70 41 (h) AFTER 50 4677 4080 7 0.7 30/70 41 (hh) AFTER 25 5601 1526 405 7.9 30/70 41 «) IP 25 1854 623 102 3.1 30/70 41 mm (1) AFTER 50 212 104 0 0.5 30/70 41 0i) AFTER 25 7094 1826 346 2.3  .30: 70th . . 41 (Ô AFTER 25 1476 1'008 17th 1.3 30/70 41 AFTER 25 11612 3709 415 2.0 30/70 41 (m) f IP 25 1864 Five hundred and first 54 2.3 30/70 41 (m) AFTER 50 9 5 0 Bologna 30/70 41 (mm) AFTER 25 2261 852 127 2.5 30/70 41 (n) IP 25 9408 1976 465 3.2 30/70 41 (n) - AFTER 50 9066 2245 253 1.9 30/70 ; 4.1 (21, IP 25 > 33750 > 5000 > 5000 • 30/70 41 (Q) AFTER 50 14717 4776 427 1.7 30/70 41 p IP 25 4150 866 380 5.5 30/70 41 (q). IP 25 > 27000 > 4000 > 4000 * 30/70

440

41 (q) AFTER 25 8572 1901 457 5.2 30/70 41 (r) IP 25 > 23752 > 5000 > 5000 • 30/70 41 (r) i PQ 50 > 17789 > 5000 > 5000 • 30/70 41 (t) AFTER 25 > 22498 > 4000 1350 4.0 30/70 41 (u) AFTER 25 875 224, 51 5.6 30/70 41 M- AFTER 25 10949 2338 749 4 _r 4 30/70 41 (X) AFTER 25 24174 4587 1268 IN 30/70 41 (yl AFTER 25 Bologna Bologna Wq. Bologna 30/70 42 (8}. IP 25 19899 4027 1639 5.0 60:40 42 (al AFTER 50 8384 3264 341 2.0 60:40 42 b IP 25 3207 953 211 3.0 60:40 42 b AFTER 50 4747 2589 46 3.0 60:40 42 (dL IP 25 1774 886 31 í ⁴ Γ 60:40 42 d AFTER 50 46 28 18 Bologna 60:40 45 (b) IP 25 11361 2636 1123 2.0 60:40 45 (b) AFTER 50 1636 427 102 3.0 60:40 47 IP 25 236 39 29 19.9 30/70 47 AFTER 50 327 84 25 3.4 30/70 59 (a) AFTER 25 50780 15878 1205 1.6 0.5% CMC 48 (a) IP 25 27000 4000 4000 • 30/70 48 (a) AFTER 25 26636 4000 3857 * 30/70 48 (b) AFTER 25 2191 476 136 4 30/70 49 (a) AFTER 25 712 342 15 30/70 49 (BLI AFTER -25 33750 5000 5000 30/70 5 (b) AFTER 10 61 . 12 3.1 60:40 _- l _t O 0? 5% OMCT 50 mm (3) r . 8 7707 . c4o9 1ZZ 59 (a) AFTER 40 57240 13798 1879 2.4 0.5% CMC 59 (a) AFTER 200 156153 29975 12117 9, ⁴ 0.5% CMC 59 (b) AFTER 50 276467 50000 26880 CMC 59 (c) AFTER 25 327135 50000 43090 CMC 59 (d) AFTER 8 > 24696 > 5000 1902 0.5% CMC 59 (d) AFTER 40 > 32297 > 5000 4135 0.5% CMC 59 (d) AFTER 200 > 123206 > 20000 12743 0.5% CMC 59 e AFTER 25 12510 28834 2135 21 0.5% CMC

In vivo test for the development of retinal vascularization in neonatal rats

The development of retinal vascularization of neonatal rats has been occurring since 1.

Postnatal day until 14.

postnatal

This process is dependent on VEGF activity (J. Stone, et al.,

J. Neurosci.,

15, 4738, the works have shown that VEGF also acts as a survival factor for retinal vessels during the early development of vascularization (Alon, et. Al, Nat. Med., 1,

1024, 1995). For

To determine the ability of specific compounds to inhibit VEGF activity in vivo, the compounds were formulated in a suitable vehicle, usually 50% polyethylene glycol, average molecular weight 400 daltones, and 50% solution of 300 mM sucrose in deionized water. Typically, two microliters (2 μΐ) of drug solution were injected into the vitreous humus of the rat pups on the 8th or 9th postnatal day. Six days after the vitreous injection, the animals were sacrificed and the retinas were dissected from other eye tissue by incision. The isolated retins were then subjected to a histochemical labeling protocol that stains endothelial cells specifically (Lutty and McLeod, Ar. Ophthalmol., 110, 267, 1992), thus revealing vascularization in a tissue sample. The individual retinas were then mounted on slides and examined to determine the extent of vascularization. The active compounds inhibited the further development of retinal vascularization and induced regression of all but the largest vessels in the retina. The degree of vascular regression was used to determine the relative potency of the compounds after in vivo administration. Vascular regression is graded on a subjective scale by one to three crosses, with one cross indicating a detectable regression judged to be about 25 percent or less, two crosses attributed to about 25-75% regression, and three crosses given to retinas with nearly total regression (about 75% or greater).

For a more accurate quantitative regression analysis, images of ADPase-labeled fixed retinas were captured by a digital camera attached to a microscope. Retina images were then imported into image analysis software (Image Pro Plus 4.0, Cybernetics Media, Silver Spring, MD). The software was used to determine the percentage of the area of the retina that contained the stained vessels. This value for the experimental eye was compared to that measured for the injected vehicle contralateral eye of the same animal. reduction

The 442 vascular region observed in the eye that received the compound compared to the vehicle injected eye was then expressed as the "percent regression for that sample." Percent regression values were averaged for groups of 5-8 animals.

In samples in which microscopic observation showed almost complete regression, a 65-70% regression percent value was routinely measured. This was due to the staining of deposits in the folds of the retina, the folds being induced by the vehicle used for drug injection. Image analysis software interpreted these folds containing the dye as blood vessels. No attempt was made to correct these folds since they varied from eye to eye. Thus, it should be noted that the percent regression values refer to the result of a conservative measurement, which, while accurately determining the order of the compounds, underestimates their absolute effectiveness.

In vivo test for the development of retinal vascularization in a model of retinopathy of premature neonatal rats

A second model of VEGF-dependent retinal neovascularization was used to evaluate the activities of this series of compounds. In this model (Penn et al., Invest. Ophthalmol. Vis. Sci., 36, 2063, 1995), rats (n = 16) with their mothers are placed in a computer controlled chamber that regulates the oxygen concentration. Animals are exposed for 24 hours at a concentration of 50% oxygen, followed by 24 hours at a concentration of 10% oxygen. This alternate cycle of hyperoxia followed by hypoxia is repeated 7 times, and then the animals are transferred to room air (P14). Compounds are injected into the vitreous after transfer to room air and animals are sacrificed 6 days later (P20). The isolated retins were then isolated, stained on a slide, and analyzed as

443 shown in detail above in the development model. Efficacy was assessed as described for the development model.

Table 7

Example # model | Initial evaluation ; inhibition Horses. (Mg / ml) PEG / water vehicle 16 (e) ROP ++ 36% 5 70:30 16 (8) ROP +++ 54% 10 70:30 W ROP ··· ++ ....... 37% 5 70:30 16 (6) ROP 4 / - 16% 1 70:30 19 (b) ROP ++ 10 70:30 19 <f) PB + / ++ 5 50:50 19φ ROP IN- 10 70:30 19 (0 ROP - 1 70:30 19 (k) ROP 10 70:30 19 (k) ROP - 1 70:30 30 (a) ROP ++ 10 70:30 30 (a) ROP ++ 48% 10 70:30 31 (8) P8 46% 5 70:30 31 (b) P8 32% 5 50:50

444

31 (C) P8 +/- var 5 50:50 31 (d) P8 12% 5 50:50 31 (e) P8 - 24% 5 50:50 32 (a) P9 20% 5 50:50 33 (b) ROP -HR 55% 10 70:30 33 (b) ROP 14% 1 70:30 33 (b) P6-P10 37% IP ' 70:30. 33 (e) P8 22% 5 70:30 33 (f) P8 20% 5 50:50 35 (a) P8 4% 5 50:50 35 (aa) P8 5 50:50 35 (c) P8 0% 5 50:50 35 (cc) P8 + / ++. 5 50:50 35 (dd) ... ____P8_. 5 50:50 35 (ee) pa + / ++ 5 50:50 35 (h) P8 +/- 5 50:50 35® PS + / ++ 5 50:50 35 (j) P8 7% 5 50:50 35 (k) pa - - - 5 ' 50:50 35 (k) Ρ8 ++ 5 50:50 35 (A) P8 20% 5 50:50 38 (a) ROP 55% 10 70:30 38 (a) ROP 16% 1 70:30 39 (b) P8 9% 5 50:50

445

4 (a) ROP ++ 10 70:30 41 (a) ROP +++ 64% of 10 70:30 41 (a) P8 0%. 0.5 50:50 41 (a) P8 ’ 4% 1 50:50 41 (a) P8 ++ / +++ 5 50:50 41 (C) ROP +++ 54% 10 70:30 41 (c) ROP +/- 16% 1 70:30 41 (c) P8 ++ - 5 50:50 41 d ROP +++ 59% 10 70:30 41 (0) ROP 0% 1 70:30 41 (e) P8 8% 5 50:50 41 (ee) P8 +/- var. 5 50:50 41 (g) P8 37% 5 50:50 W five -0% - --5 ~ - -70: 30- 410) P8 + / ++ 5 50:50 41 k P8 1% 5 50:50 41 (1) P8 28% 2.5 70:30 41 (m) P8 10% 5 .50: 50 41 mm - - P8- + ------- - - 5 - - 50: 50- 41 (n) P8 2% 5 50:50 41 (0) P8 2% 5 50:50 41 (p) P8 35% 5 50:50 41 (r) ΡΘ +/- var. 5 50:50 ROP -H- + 23% 10 70:30

446

42 (a) ROP + 1% 1 70:30 42 (a) ROP + 10 70:30 42 (a) P9 55% 10 70:30 42 (a) P6-P10 61% ip * 70:30 42 (a) Ρ8 + / ++ 5 50:50 42 (b) P9 40% 10 70:30 42 (C) P8 36% 5 50:50 45 (b) ' ROP ++ 60% 10 70:30 45 (b) ROP -h / - 25% 1 70:30 49 (a) P8 54% 5 50:50 49 (b) P8 5% 5 50:50 5 (b) ROP ++ 45% 5 70:30 59 (a) ROP 41% 10 0.5% CMC 59 (a) ROP 19% 1 0.5% CMC 6 (a) ROP ++ 5 65:35 6 (b) ROP ++ 10 70:30

Phosphorylase kinase

Phosphorylase Kinase Construct for Assay

A truncated catalytic subunit (gamma subunit) of phosphorylase kinase (amino acids 1 to 298) was expressed in E. Coli and isolated from inclusion bodies. The kinase phosphorylase was then refolded and stored in glycerol at -20 ° C.

447

Phosphorylase kinase assay.

The purified catalytic subunit was used in the assay to phosphorylate phosphorylase bs using radiolabeled ATP. Briefly, 1.5 mg / ml phosphorylase b was incubated with 10nM phosphorylase kinase in 10mM MgCl _{2 from} 50mM Hepes, pH 7.4, at 37 ° C. The reaction was started by adding ATP to 100 μ do and incubated for 15 minutes at 25 ° C or 37 ° C. The reaction was terminated and proteins were precipitated by adding TCA to 10% final concentration. Precipitated proteins were isolated on 96-well Millipore MADP NOB filter plates. The filter plates were then thoroughly washed with 20% TCA and dried. Scintillation fluid was then added to the plates and the radiolabel incorporated was counted on a Wallac beta beta counter. % inhibition of phosphate transfer from ATP to phosphorylase b in the presence. 10 μΜ of the compound is shown in Table 8 below.

Table 8

Example # % inhibition @ 10 μΜ 52 (b) 92 27 (f) ⁹⁰ 27 (a) 37

Examples of the compound described above can be formulated into pharmaceutical compositions according to the following general examples.

448

Example 1

Parenteral preparation

To prepare a parenteral pharmaceutical formulation suitable for injection, 100 mg of the water-soluble salt of the compound of formula I was dissolved in DMSO, and then mixed with 10 mL of 0.9% sterile saline. The composition is formulated in a unit dosage form suitable for administration by injection.

Example 2

Oral preparation

In order to prepare a pharmaceutical composition for oral administration, 100 mg of a compound of formula I was mixed with 750 mg of lactose. The mixture was formulated into an oral dosage unit, such as a hard gelatin capsule, suitable for oral administration.

Example 3

Intraočný príprava

In order to prepare a sustained release pharmaceutical composition for intraocular administration, the compound of formula I was suspended in a neutral, isotonic solution of hyaluronic acid (1.5% conc.) In phosphate buffer (pH 7.4) to form a 1% suspension.

449

It is to be understood that the foregoing description is given by way of example and explanation of preferred embodiments explaining the nature, and is intended to illustrate the inventions and preferred embodiments thereof. Based on routine experiments, one of ordinary skill in the art will readily find modifications and variations that can be made without departing from the inventive idea. Accordingly, it is intended that the scope of the invention is not defined by the above description but by the appended claims and their equivalents.

Claims (17)

PATENT CLAIMS 450 1. A compound of formula I: where: R ¹ is an unsubstituted aryl group or a substituted or unsubstituted heteroaryl group or group CH = CH-R ³ or CH = NR ³ , wherein R ³ is a substituted formula or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl, and R ² is a substituted or unsubstituted aryl group, a heteroaryl group or a group YX wherein Y is O, S, C = _CH2, C = O, S = O, _SO2, alkylidene, NH or N-alkyl containing 1 to 8 carbon atoms and X is substituted or unsubstituted Ar, heteroaryl, NH-alkyl, NH-cycloalkyl, NHheterocycloalkyl, NH-aryl, NHheteroaryl, NH-alkoxy or NHdialkylamido wherein Ar is aryl, or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof. 451 2. Compound of Formula I (a): where: R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ³ or CH = NR ³ , wherein R ³ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group and R ² is a substituted or unsubstituted aryl or Y-Ar, where Y is O, S, C = _CH2, C = 0, S = 0, a group of S0 _2, CH _2, a group CH-CH _3, an NH or N-C 1 -C 8 -alkyl group and Ar is a substituted or unsubstituted aryl group, or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite or pharmaceutically acceptable salt thereof. 3. The compound of formula II: 452 where: R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ³ or CH = NR ³ , wherein R ³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, R ⁴ and R ⁷ are each independently hydrogen, OH, halogen, C 1 -C 8 alkyl, C 1 -C 8 alkoxy, C 1 -C 8 alkenyl, aryloxy, thioaryl, CH _2- OH, CH ₂ -O-alkyl of 1 to 8 carbon atoms, CH ₂ -O-aryl, CH ₂ -Salkyl of 1 to 8 carbon atoms or CH ₂ -Saryl, R ⁵ and R ⁶ are each independently hydrogen, OH, halogen, Z-alkyl, Z-aryl or Z-CH ₂ CH = CH ₂ , wherein Z is O, S, NH or CH ₂ and the alkyl group and the aryl group of the Z-alkyl group and the Zaryl group are each optionally substituted, or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof. The compound, a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite or a pharmaceutically acceptable salt thereof according to claim 3, wherein: R ¹ is a substituted or unsubstituted bicyclic heteroaryl group or a group of formula CH = CH-R, wherein R is a substituted or unsubstituted aryl or heteroaryl group, 453 R ⁴ and R ^{7 are} each independently hydrogen or C 1 -C 8 alkyl; R ⁵ and R ⁶ are each independently halogen, Z-alkyl or Z-CH ₂ CH = CH ₂ , wherein Z is O or S and the alkyl group is optionally substituted. 5. The formula III formula: H H where: R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ³ or CH = NR ³ , wherein R ³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , CH ₂ , CHCH 3, NH or C 1 -C 8 -alkyl, R ⁸ is substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy or aryloxy, R ¹⁰ is independently selected from the group consisting of hydrogen, halogen and lower alkyl 454 or a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite, and a pharmaceutically acceptable salt thereof. A compound, a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt thereof according to claim 5, wherein: R ¹ is a substituted or unsubstituted bicyclic heteroaryl group or a group of formula CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted aryl or heteroaryl group, Y is O, S, C = CH ₂ , C = O, NH or N-C 1 -C 8 -alkyl, R 8 is a substituted or unsubstituted aryl, heteroaryl, alkyl and alkenyl group and R ¹⁰ is a hydrogen atom or a halogen atom. 7. Compound of formula III (a): where: R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ³ or CH = NR ³ , wherein R ³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, 455 Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , CH ₂ , CHCH ₃ , NH or N-alkyl containing up to 8 carbon atoms, R ⁸ is a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy or aryloxy group, or a pharmaceutically acceptable prodrug, pharmaceutically active metabolite, or pharmaceutically acceptable salt thereof. A compound, a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt thereof according to claim 7, wherein: R ¹ is a substituted or unsubstituted bicyclic heteroaryl group or a group of formula CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted aryl or heteroaryl group, Y is O, S, C = CH ₂ , C = O, NH or N-C 1 -C 8 alkyl; and R ⁸ is a substituted or unsubstituted aryl, heteroaryl, alkyl or alkenyl group. A compound, a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt thereof according to claim 7, wherein: R ¹ is CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted aryl group, Y is O or S and 456 R ⁸ is a substituted or unsubstituted aryl or heteroaryl group. A compound of formula IV. R ¹ is a substituted or unsubstituted aryl or heteroaryl group or a group of formula CH = CH-R ³ or CH = NR ³ , wherein R ³ is a substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl or heteroaryl group, Y is O, S, C = CH ₂ , C = O, S = O, SO ₂ , CH ₂ , CHCH ₃ , NH or C 1 -C 8 -alkyl, R ⁹ is substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl, heteroaryl, alkoxy, aryloxy, cycloalkoxy, NH 1 -C 8 alkyl, NH-aryl, NH-heteroaryl, N = CH-alkyl, NH (C = O) ^RU or NH _2, wherein R ¹¹ is independently selected from the group consisting of hydrogen, substituted or unsubstituted alkyl, cycloalkyl, heterocycloalkyl, aryl and heteroaryl, and R ¹⁰ is independently selected from the group consisting of hydrogen, halogen and lower alkyl 457, or a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite, and a pharmaceutically acceptable salt thereof. The compound, a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt thereof according to claim 10, wherein: R ¹ is a group of formula CH = CH-R ³ , wherein R ³ is a substituted or unsubstituted aryl or heteroaryl group, Y is S or NH and R ⁹ is a substituted or unsubstituted alkyl, alkoxy or NH-heteroaryl group. A compound, a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt thereof, selected from the group consisting of: 458 459 460 461 13. A pharmaceutical composition comprising: (a) a therapeutically effective amount of a compound, a pharmaceutically acceptable prodrug thereof, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt thereof according to claim 1; and (b) a pharmaceutically acceptable carrier, diluent, or vehicle. 14. A method of treating a disease state of a mammal mediated by protein kinase activity, comprising administering to the mammal in need thereof a therapeutically effective amount of a compound, a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt as defined in claim 13. The method of claim 14, wherein the mammalian disease state is associated with tumor growth, cell proliferation, or angiogenesis. 16th A method of modulating the activity of a protein kinase receptor comprising contacting a kinase receptor with an effective amount of a compound, a pharmaceutically acceptable prodrug, a pharmaceutically active metabolite, or a pharmaceutically acceptable salt as defined in claim 13. 17. The method of claim 16, wherein the protein kinase receptor is a VEGF receptor.